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Regulation of LaeA and Velvet Proteins on the Production of Mycotoxins and Other Fungal Secondary Metabolites

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15 July 2024

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16 July 2024

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Abstract
Fungi are rich sources of secondary metabolites of agrochemical, pharmaceutical and food importances, such as mycotoxins, antibiotics and antitumor agents. Secondary metabolites play vital roles in fungal pathogenesis, growth and development, oxidative status modulation, and adaptation/resistance to various environmental stresses. LaeA contains an S-adenosylmethionine binding site and displays methyltransferase activity. The members of velvet proteins include VeA, VelB, VelC, VelD and VosA, for each member with a velvet domain. LaeA and velvet proteins can form multimeric complexes such as VosA-VelB and VelB-VeA-LaeA. They belong to global regulators and are mainly impacted by light. One of their most important functions is to regulate gene expression that are responsible for secondary metabolite biosynthesis. The aim of this mini-review is to represent the newest cognition on the biosynthetic regulation of mycotoxins and other fungal secondary metabolites by LaeA and velvet proteins. In most cases, LaeA and velvet proteins positively regulated production of fungal secondary metabolites. The regulated fungal species mainly belong to the toxigenic fungi from the genera of Alternaria, Aspergillus, Botrytis, Fusarium, Magnaporthe, Monascus, and Penicillium for the production of mycotoxins. We can control secondary metabolite production to inhibit the production of harmful mycotoxins while promoting the production of useful metabolites by global regulation of LaeA and velvet proteins in fungi. Furthermore, the regulation by LaeA and velvet proteins should be a practical strategy in activating silent biosynthetic gene clusters (BGCs) in fungi to obtain previously undiscovered metabolites.
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Subject: Biology and Life Sciences  -   Life Sciences

1. Introduction

Fungal secondary metabolites are highly complex and have a rich diversity that makes fungi a treasure of bioactive secondary metabolites [1,2,3,4]. Some fungal metabolites are harmful to plants, humans and animals, which are usually called mycotoxins [5,6,7,8]. Many bioactive metabolites derived from fungi display their broad potential as agrochemicals, pharmaceuticals, cosmetics and food additives [9,10].
In recent years, it has become easier through genome mining to identify and functionally predict fungal metabolites [11]. Many strategies can regulate (i.e., promote or inhibit) the biosynthesis of secondary metabolites in fungi such as one strain-many compounds (OSMAC), global regulation, epigenetic regulation, heterologous expression, and combinatorial biosynthesis [12,13,14]. Among them, global regulation for secondary metabolite production has been thought to be the most practical strategy. Global regulation is a complex upper-level regulatory network in which microorganisms respond comprehensively to external environmental stimuli such as light intensity, temperature, ambient pH, redox status, carbon and nitrogen sources. LaeA and velvet proteins belong to global regulators, and are mainly regulated by light. Both LaeA and velvet proteins can form multimeric complexes. They are involved in fungal development and secondary metabolism [15,16,17,18,19].
In the past 20 years, many advances have been achieved about the regulation of LaeA and velvet proteins on fungal secondary metabolism and development. Though some reviews were published [15,20,21], many other recent achievements have not been included. In this review, we focused on the regulation of LaeA and velvet proteins on secondary metabolite production in fungi, in order to inhibit the production of mycotoxins, promote the production of useful metabolites, reveal previously undiscovered metabolites, clarify their regulation mechanisms, and accelerate their applications.

2. Regulation of LaeA on Secondary Metabolite Production in Fungi

LaeA (loss of aflR expression) is also called Lae1 or LAE1. It was first identified as a nuclear protein in Aspergillus. Compared to the velvet proteins, LaeA has no velvet domain [16]. LaeA functions as a global regulator of secondary metabolism and morphogenetic development in various filamentous fungi. LaeA protein sequence contained an S-adenosylmethionine binding site, so it has been proposed to have methyltransferase activity, and might linked to the remolding of chromatin structure to regulate gene transcription by lysine or arginine methylation of histone [22,23]. In most cases, the laeA genes in fungi positively regulated production of secondary metabolites. Only a few laeA genes were found to negatively regulate secondary metabolite production (Table 1) [21]. At present, the regulation studies of LaeA mainly focuses on the toxin-producing fungal species for mycotoxin control, as well as plant endophytic fungi and marine-derived fungi for mining bioactive compounds. Some examples of LaeA regulating secondary metabolite production in fungi are shown in Table 1. The structures of the metabolites are shown in Figure S1.
Overexpression of AaLaeA increased production of antitumor compounds including myricetin (1), geraniol (2), ergosterol (3) and other compounds in the endophytic fungus Alternaria alstroemeria by metabolomic analysis [24]. In contrast, overexpression of AaLaeA in another endophytic fungus A. alstroemeria derived from the medicinal plant Artemisia annua decreased production of antitumor compounds. Unfortunately, the antitumor compounds were not further identified [25]. Many species in Alternaria genus usually belong to the plant pathogenic fungi to produce host-specific toxins (HSTs) and cause host plant diseases [2]. A. alternaria was the pathogen of some plants such as tomato, apple and strawberry to produce AAL-, AM- and AF-toxins, respectively. It was found that LaeA positively regulated production of the HSTs as well as development and pathogenicity of A. alternaria [26]. In other instances, deletion of laeA in A. alternata greatly decreased the production of alternariol (AOH, 4) and alternariol monomethyl ether (AME, 5) [27]. Furthermore, overexpression of a LaeA-like global transcriptional regulator in marine-derived fungus A. alternata JJY–32 led to the discovery of an anti-inflammatory meroterpenoid namely tricycloalternarene O (6) [28].
Arthrobotrys flagrans (synonym Duddingtonia flagrans) was a typical nematode-trapping fungus which has been used for nematode biocontrol. Overexpression or deletion of AfLaeA positively regulated production of secondary metabolites and their antinematodal activity, whereas some metabolites were not produced due to the absence of AfLaeA. The antinematodal activity of these secondary metabolites needs further confirmation [29].
There are many examples of Aspergillus species regulated by LaeA to produce secondary metabolities (Table 1). Overexpression of Az5LaeA in Aspergillus sp. Z5 exhibited increased production of diorcinol (7). The laeA (AnLaeA) gene from A. nidulans was heteroexpressed in Aspergillus sp. Z5, and was also found to increase production of diorcinol (7) [30]. Introduction of laeA from A. nidulans to Aspergillus sp. FKI-5362 led to an increase in production of an antifungal compound MS-347a (8), which could inhibit the growth of broad plant pathogenic fungi including Botrytis cinerea, Colletotrichum gloeosporoides, Leptosphaeria maculans, and Pyricularia oryzae [31]. MS-347a (8) was previously screened to inhibit myosin light chain kinase from Aspergillus sp. KY52178 [32]. When laeA gene was deleted in A. carbonarius, the production of citric acid (9) [33] and ochratoxin A (OTA, 10) [34,35] was greatly decreased, respectively. If the deleted mutant ΔlaeA of A. carbonarius was colonized in nectarines and grapes, OTA (10) was significantly reduced [35]. When A. carbonarius was treated with eugenol at 0.2 μL/mL, OTA (10) production was decreased at 87.7%. The transcription of the clustered genes for OTA biosynthesis was significantly reduced under eugenol stress and was further confirmed by RT-qPCR analysis. The expression of LaeA was markedly downregulated by eugenol, which indicated that eugenol was probable through inhibiting LaeA expression to decrease OTA (10) production in A. carbonarius [35].
Overexpression of llm1 encoding LaeA-like methyltransferase in A. cristatus led to an increase of contents of multiple secondary metabolites including terpenoids and flavonoids. Unfortunately, these metabolites were not identified [37]. With a scaled-up fermentation of the ΔflLaeA strain of A. flavipes, five metabolites, including two previously undescribed piperazine derivatives flavipamides A (11) and B (12), along with three known nonribosomal peptides asperphenamate (N-benzoylphenylalaniny-N-benzoylphenyl-alaninate, 13), 4′-OMe-asperphenamate (14), cyclic Pro-Gly-Val-Gly-Try(8-OH, 3-prenyl)-Gly-Trp (15) were obtained by LC-MS guided isolation [38].
Aflatoxins (AFs) have been thought of as the most potent carcinogens, and some fungal species from Aspergillus genus are their main producers, especially A. flavus. LaeA was revealed to positively regulate production of alfatoxins in A. flavus [39,40,41,42]. Deletion of laeA in A. flavus resulted in the significant upregulation of the NAD+-dependent histone deacetylase sirA involved in silencing secondary metabolism clusters via chromatin remodeling. Accompanying the chromatin modification, the enzymes participating in secondary metabolism, including biosynthesis of sterigmatocystin (ST, 16), aflatoxin B1 (17), cyclopiazonic acid (18) and ustiloxin B (19), were drastically decreased [40,43,44]. The enzymes in the ustiloxin B (19) biosynthesis pathway might be indirectedly regulated by LaeA [44]. An interaction partner of LaeA namely kinetochore protein Spc105 was revealed to regulate development and secondary metabolism in A. flavus. Moreover, Spc105 positively regulated the production of secondary metabolites such as aflatoxins and kojic acid (20), and negatively regulated the production of cyclopiazonic acid (18). Transcriptome analysis of the Δspc105 mutant revealed that 23 backbone genes for secondary metabolism were differentially expressed, corresponding to 19 of the predicted 56 secondary metabolite gene clusters, suggesting a broad regulatory roles of Spc105 on secondary metabolism in A. flavus [45].
The production of several mycotoxins was positively regulated by LaeA in A. fumigatus. For examples, the deletion of laeA led to decreased production of gliotoxin (21), endocrocin (22), fumagillin (23), fumagatin (24), and helvolic acid (25) in several strains of A. fumigatus [46,47,48,49]. Production of cyclopiazonic acid (18) was increased when laeA was overexpressed in A. fumisynnematus [50]. Deletion of laeA gene in A. luchuensis mut. kawachii led to the reduced production of citric acid (9). LaeA was considered as the methyltransferase through regulating citrate exporter-encoding cexA gene [51].
Overexpression of laeA in A. nidulans led to an increased production of sterigmatocystin (16) [52] and terrequinone A (26) [53]. Accordingly, the deletion of laeA gene in A. nidulans reduced the production of sterigmatocystin (16) and norsolorinic aid (NOR, 27) [54]. The deletion of laeA also led to a depressed expression of genes involved in biosynthesis of sterigmatocystin (16), terrequinone A (26) and penicillin G (benzylpenicillin, 28) [55]. However, a contradictory example was that the deletion of laeA gene in A. nidulans also led to an increased production of sterigmatocystin (16) [56]. Generally, LaeA or LaeA-like methyltransferase F (LlmF) negatively regulated biosynthesis of sterigmatocystin (16) in A. nidulans.
Aspergillus niger is a biotechnologically important filamentous fungus and has been thought of as an industrial cell factory for the production of secondary metabolites with a broad spectrum of application fields covering agriculture, food, and pharmaceutical industry [57]. Deletion of laeA in A. niger decreased production of asperrubrol (29), atromentin (30) and JBIR 86 (31), but increased production of aspernigrin A (32) and BMS-192548 (33), which meant that LaeA positively regulated production of asperrubrol (29), atromentin (30) and JBIR 86 (31), and negatively regulated production of aspernigrin A (32) and BMS-192548 (33) in A. niger [58]. Overexpression of laeA gene in A niger led to an activation of secondary metabolite BGCs in the mutant. Three compounds including flaviolin (34), orlandin (35) and kotanin (36) were identified [59]. LaeA could influence the secondary metabolite profile in A. niger FGSC A1279 based on the genome sequencing and transcriptome analysis [60]. The production of ochratoxin A (OTA, 10) in A. niger was decreased in the deleted mutant and increased in the overexpressed mutant. Another similar example was that deletion of laeA gene in A. ochraceus led to the reduced production of OTA (10) [61]. This indicated that LaeA positively regulated gene expression of OTA (10) BGC in A. niger and A. ochraceus. In contrast, it was found that the upregulation of gene expression of OTA BGC did not necessarily increase OTA (10) production in A. niger [62].
Kojic acid (20) production was inhibited in the laeA disruption strain of A. oryzae, and restored in the laeA complement strain, which meant that LaeA positively regulated biosynthesis of kojic acid (20) in A. oryzae [63]. In the expression system of A. oryzae, LaeA also showed its positive regulation on the heterologous BGCs. Overexpression of laeA resulted in the increased production of monocolin K (MK, 37) and terrequinone A (TQ, 38). The successful production of secondary metabolites belonging to different structural groups, namely MK (37) as a polyketide, and TQ (38) as a hybrid of amino acid and isoprenoid, indicated that the laeA-enriched A. oryzae was a versatile host for the heterologous expression of the biosynthetic gene clusters such as the BGC of MK (37) from Monascus pilosus, and the BGC of TQ (38) from A. nidulans [64]. For A. pachycristatus and A. pseudoterreus, the production of secondary metabolites was also positively regulated by LaeA [65,66]. Production of sterigmatocystin (16) and echinocandin B (ECB, 39) was decreased in laeA deleted mutant of A. pachycristatus [65]. Overexpression of laeA in A. pseudoterreus improved itaconic acid (40) yield at the expense of biomass by increasing the expression of key biosynthetic pathway enzymes and attenuating the expression of genes involved in phosphate acquisition and scavenging. Increased yield was observed in optimized conditions as well as conditions containing excess nutrients that might be present in inexpensive sugar containing feedstocks such as excess phosphate or complex nutrient sources [66].
A. terrreus is the main industrial producer of lovastatin (41), a drug to lower cholesterol. Lovastatin (41) is also used as a precursor for simvastatin production. In A. terreus, the overexpression of laeA gene triggered the increase of gene transcription related to penicillin G (28) and lovastatin (41) biosynthesis [43]. It has been observed that overexpression of laeA gene in A. terreus increased the production of lovastatin (41) [67,68]. Chemical epigenetic modifiers 1,3-diaminopropane and spermidine also upregulated lovastatin (41) production and expression of lovastatin (41) biosynthetic genes in A. terreus via LaeA regulation [69]. Overexpression of laeA in A. terreus resulted in the activation of a silent secondary metabolite cluster without corresponding known metabolites. The yields of two antibacterial alkaloids dihydroisoflavipucines 1 (42) and 2 (43) reached 183 mg/L and 1.55 mg/mL, respectively. Both compounds showed obviously anti-Vibrio activities with the MIC values ranging from 16 to 64 μg/mL against Vibrio anguillarum, V. campbellii, V. harveyi and V. vulnificus [70].
The production of beauvericin (44) and bassiatin (45) was reduced in the BbLaeA disruption strain of Beauveria bassiana, but was increased in the overexpressed strain [71].
The production ability of oxalic acid (OA, 46) was lost in laeA disruption strain of Botryitis cinerea [72]. Another example was that the production yield of abscisic acid (ABA, 47) was decreased 90% in laeA disruption strain of B. cinerea. It was considered that BcLAE1 was involved in epigenetic regulation as a methyltransferase, with enhanced H3K9me3 modification and attenuated H3K4me2 modification in ΔBclae1 mutant of B. cinerea [73].
Overexpression of laeA in Chaetomium globosum CBS148.51 up-regulated expression of the chaetoglobosin BGC and resulted in the isolation of seven cytochalasans including chaetoglobosins A (48), B (49), D (50), E (51), O (52), V (53) and Z (54). Of them, chaetoglobosin Z (54) was a new cytochalasan. These cytochalasans displayed strong cytotoxic activity against the HepG 2 cell line [74]. Similarly, the production of chaetoglobusin A (48) in ΔCglaeA mutant of another C. globosum strain was inhibited, its CglaeA-C strain restored the production of chaetoglobusin A (48), and the strain of CglaeA overexpression led to an increase in chaetoglobusin A (48). It indicated that LaeA positively regulated the production of chaetoglobusin A (48) in C. globosum [75].
Cladosporium fulvum was the non-obligate biotrophic fungal tomato pathogen. Deletion of laeA in C. fulvum led to the increased production of the mycotoxin cladofulvin (55), which meant that LaeA negatively regulated biosynthesis of cladofulvin (55) in this fungus [76].
T-toxin (56) was a host selective phytotoxin produced by maize pathogen Cochliobolus heterostrophus. Deletion of Chlae1 decreased production of T-toxin (56) in C. heterostrophus [77].
Coprinoferrin (57) was an acylated tripeptide hydroxamate consisting of tandem aligned N5-hexanoyl-N5-hydroxy-L-ornithine with modifications of N-acetyl and C-carboxamide. Knockout of laeA in the mushroom fungus Coprinopsis cinerea upregulated the biosynthesis of a novel siderophore namely coprinoferrin (57), which indicated that LaeA negatively regulated production of coprinoferrin (57) [78]. The unique chemical properties made coprinoferrin (57) an iron (III) binder (siderophore), which helped iron acquisition from the environment and promoted hyphal growth as well as fruiting body formation in C. cinerea. In addition, coprinoferrin (57) could be chemically synthesized from N-Boc-L-glutamic acid 5-benzyl ester [79].
Daldinia eschscholzii was an endophytic fungus from the guts of mantis (Tenodora aridifolia). Replacement of the native promoter of the global regulator LaeA-like gene of D. eschscholzii by a strong gpdA promoter led to the generation of two novel cyclopentenone metabolites, named dalestones A (58) and B (59). Both dalestones inhibited the gene expression of TNF-α and IL-6 in LPS-induced RAW264.7 macrophages [80].
Deletion of DsLaeA resulted in enhanced production of dothistromin (60) in the pine needle pathogen Dothistroma septosporum, and increased expression of the regulatory gene DsAflR in dothistromin (60) biosynthetic pathway [81].
Fusarium fujikuroi (teleomorph: Gibberella fujikuroi) is the pathogen of rice bakanae disease to produce a series of secondary metabolites such as bikaverin (61), fusaric acid (62), gibberellins, fusarins, and fusarubins. Among them, fusaric acid (62) and fusarins belong to the harmful mycotoxins [82]. LaeA positively regulated production of some metabolites in F. fujikuroi. For examples, deletion of laeA in F. fujikuroi led to decreased production of gibberellins A3 (63) and A4 (64), fusarin C (65), fumonisins B1 (66), B2 (67), B3 (68) and B4 (69), deoxynivalenol (70), and 15-acetyl deoxynivalenol (71) [83]. The similar results were subsequently confirmed. Deletion of lae1 gene led to reduced production of fusaric acid (62), fusarinolic acid (72), and dehydrofusaric acid (73) in F. fujikuroi strain [84]. Furthermore, deletion of lae1 led to decreased production of gibberellins, fumonisins and fusarin C (65). Overexpression of lae1 led to increased production of gibberelins in another F. fujikuroi strain [85]. However, LaeA also negatively regulated production of some metabolites in F. fujikuroi. The production of bikaverin (61) was increased in the deletion mutant of F. fujikuroi [83]. Another example was that deletion of lae1 gene in F. fujikuroi led to upregulation of gibepyrone BGC expression as well as increased production of gibepyrones A (74), B (75), C (76), D (77), E (78), and F (79) [86].
LaeA positively regulated mycotoxin production of the following phytopathogenic Fusarium species. Deletion of FglaeA in F. graminearum led to a dramatic reduced production of trichothecenes and zearalenone (80). Overexpression of FglaeA caused the increased production of trichothecenes and zearalenone (80). This indicated that FgLaeA positively regulated production of phytotoxins of F. graminearum [87]. For the fungus F. oxysporum, deletion of laeA caused the decreased production of beauvericin (44) and fusaric acid (62), which contributed to virulence on plant hosts such as tomato plants [88]. For the fungus F. oxysporum f.sp. niveum, the deletion of FoLae1 gene led to depressed conidiation and reduced production of fusaric acid (62) and bikaverin (70). In addition, all of these alterations in the deleted mutants were restored in the corresponding complementation strains. [89]. For the fungus F. verticillioides, the deletion of laeA reduced production of fusaric acid (62), fusarin C (65), bikaverin (70), and fumonisins [90].
Ganoderic acids (GAs) are lanosterol-type triterpenoids produced by Ganoderma species that possess multiple bioactivities including anti-cancer, anti-inflammatory, antioxidant, and anti-HIV activities [91]. When a methyltransferase-like laeA gene was deleted in G. lingzhi, the production of ganoderic acids was reduced. RT-qPCR analysis further revealed that the transcription levels of genes involved in the biosynthesis of garnoderic acids were drastically lower in the ΔlaeA strain. In contrast, constitutive overexpression of laeA resulted increased concentration of GAs [92].
Magnaporthe oryzae causes blast disease, the most serious disease of cultivated rice affecting global rice production. MolaeA negatively regulated sporulation and melanin biosynthesis, and positively regulated production of penicillin G (or called benzylpenicillin, 28) [93]. Metabolomic profiling analysis showed that overexpression of MolaeA led to increased biosynthesis of secondary metabolites in M. oryzae. Unfortunately, these metabolites have not been identified [94].
Some Monascus species can produce edible pigments, with their structures bearing a highly oxygenated pyranoquinone bicyclic core and a quaternary carbon center. However, the mycotoxin citrinin (81) produced by some Monascus strains restricts application of the pigments [95]. Monacolin K (37), a cholesterol-lowering agent, was increased for 3 times when laeA was overexpressed in Monascus pilosus. In addition, the pigment production was also remarkably increased [96]. The production of monacolin K (37) was also increased when laeA was overexpressed in M. purpureus [97]. For another Monascus species, the deletion of MrlaeA in M. ruber exhibited drastically reduced production of toxin citrinin (CIT, 81) and six pigments including rubropunctamine (82), monascorubramine (83), monascin (84), rubropunctatin (85), ankaflavin (86), and monascorubrin (87) [98].
The laeA gene from Aspergillus nidulans was heteroexpressed in the fungus Penicillium sp. LC1-4. Overexpression of AnLaeA caused an increased production of a bioactive compound quinolactacin A (88). It indicated that heteroexpressed of AnLaeA in fungi was a simple and effective method to explore metabolic potential [30]. LaeA could also positively regulate production of antibacterial pseurotins in Penicillium sp. Deletion of laeA gene in Penicillium sp. strain MB inhibited production of the members with 1-oxa-7-aza-spiro[4,4] non-2-ene-4,6-dione skeleton. Among these deduced compounds, pseurotins A (89), B (90), C (91), D (92), and E (93) displayed obvious antibacterial activity. It was why cheese rind bacterial communities assembled with the laeA deletion mutant of Penicillium sp. strain MB had significantly higher bacterial abundances than the wild-type strain [99].
To date, secondary metabolite production of Penicillium species have been found to be positively regulated by LaeA. Overexpression of PbrLaeA led to the discovery of four compounds including fumigatin chlorohydrin (94), iso-fumitatin chlorohydrin (95), spinulosin (96) and pyranonigrin F (97) in the fungus P. brocae HDN-12-143. Among them, iso-fumitatin chlorohydrin (95) was a new compound. Both fumigatin chlorohydrin (94) and iso-fumitatin chlorohydrin (95) exhibited cytotoxic activity against HL-60 with IC50 values of 18.63 µM and 24.83 µM, respectively [100]. Overexpression of PclaeA in P. chrysogenum gave rise to 25% increase production of penicillin G (benzylpenicillin, 28). PclaeA knock-down mutants exhibited drastically reduced production and biosynthesis gene expression of penicillin G (28) [22]. Deletion of laeA in P. chrysogenum decreased production of penicillin G (28) [101]. However, epigenetic modifiers 1,3-diaminopropane (1,3-DAP) and spermidine completely restored the levels of penicillin G production in the laeA knock-down mutant. This indicated that LaeA in P. chrysogenum might act epigenetically on the expression of secondary metabolite genes by heterochromatin reorganization, which should be studied in detail [102]. Small reduction of penicillin G (28) was also reported in another ΔPclaeA mutant of P. chrysogenum [103]. The full-length laeA gene namely Pci-laeA with the sequence as 1,340 bp including an ORF of 1,284 bp encoding 427 amino acids was cloned from P. citrinum. The predicted molecular mass of Pci-LaeA was 48.72 kDa with an estimated theoretical isoelectric point of 6.96. Pci-LaeA had a conserved S-adenosylmethionine binding site and a potential MlcR (a pathway specific regulator in mevastatin biosynthesis) binding site [104]. When laeA gene was deleted in P. citrinum, production of compactin (also named ML-236B, mevastatin, 98) was suppressed [105]. Comparative transcriptome analysis revealed that the function loss of PdLaeA in P. digitatum resulted in the reduced expression of several secondary metabolite gene clusters [106].
Sorbicillinoids are important hexaketide metabolites derived from fungi. They have a variety of biological activities with unique structural features to make them attractive candidates for developing new pharmaceutical and agrochemical agents [107,108]. Overexpression of laeA gene in the marine-derived fungus P. dipodomyis YJ-11 induced metabolic variations to afford a series of sorbicillinoids including two new ones named 10,11-dihydrobislongiquinolide (99) and 10,11,16,17-tetrahydrobislongiquinolide (100), as well as four known analogues, bislongiquinolide (101), 16,17-dihydrobislongiquinolide (102), sohirnone A (103), and 2’,3’-dihydrosorbicillin (104). This indicated that regulation of LaeA is a useful strategy in activating silent gene clusters in fungal strains to obtain previously undiscovered compounds [109].
The mycotoxin patulin (105) is produced in the colonized tissue by P. expansum during storage of apples. Deletion of laeA in P. expansum led to a decrease of patulin (105) production, which positively regulated patulin gene expression and patulin biosynthesis. Loss of LaeA affected the colonization of P. expansum in apple fruits. The ΔlaeA strains showed reduced virulence at all stages of apple maturity, and the disease severity was reduced by up to 22% in more mature fruits [110,111]. It demonstrated that patulin metabolism modulated by LaeA contributed in part to pathogenicity of P. expansum [110].
The LaeA in P. oxalicum played important roles in asexual development, expression of secondary metabolite gene clusters, and extracellular glycoside hydrolase synthesis. Deletion of laeA gene led to decreased production of secondary metabolites. Unfortunately, these differential metabolites have not been identified [112]. Four (i.e., cluster_1, cluster_5, cluster_14, and cluster_26) of the 28 secondary metabolic gene clusters were significantly downregulated in ΔlaeA mutant compared with wild type strain (WT) of P. oxalicum. The LaeA was speculated as the putative methyl-transferase. Histone H2B lysine 122 and lysine 130 were considered as the putative targets of LaeA [113]. Another example was that the disruption of PrlaeA in P. roqueforti led to a substantial reduction in the production of the three metabolites roquefortine C (106), mycophenolic acid (107), and andrastin A (108). However, deletion of PrlaeA had little impact on asexual development [114].
Disruption of laeA in Pestalotiopsis microspore led to the decreased production of pestalotiollide B (PB, 109) [115]. Similarly, deletion of PoLaeA1 in Pleurotus ostreatus decreased the intracellular polysaccharide (IPS) content by about 28-30% as well as cellulose activity, which provided new insights into the regulation of polysaccharide biosynthesis and cellulose production in filamentous fungi [116]. PoLAE1 also positively regulated tenuazonic acid (TeA, 110) production of rice blast pathogen Pyricularia oryzae (teleomorph: Magnaporthe oryzae) [117].
LaeA positively regulated secondary metabolite production of the following Trichoderma species. Overexpression of TalaeA in T. afroharzianum led to production of two new antifungal polyketides: (1R,3E,5E)-1-(3,5-dihydroxy- 2,4-dimethylphenyl)-1-hydroxyhepta- 3,5-dien-2-one (111) and (1R,3E,5E)-1-(3,5-dihydroxy- 2,4-dimethylphenyl)-1-methoxyhepta- 3,5-dien-2-one (112). Both compounds showed strong antifungal activity on plant pathogenic fungi Botrytis cinerea, Colletotrichum lagenarium and Fusarium oxysporum f.sp. nicotianae [118]. Deletion of Tllae1 in T. longibrachiatum reduced the production of peptaibols to a large degree. The peptaibols belonged to antimicrobial peptides and were named as trichokonins (TKs) which were mainly classified into 20-aa trichokonin A (TKA) and 12-aa trichokonin B (TKB). Overexpression of Tllae1 in T. longibrachiatum led to 2-fold increased production of petaibols. Overexpression of laeA gene in T. reesei led to the increased production of sorbicillinoids, which were not identified. If the laeA gene in another T. reesei strain was deleted, the production of sterigmatocystin (16) was decreased [119]. T. reesei had a potential to produce terpenoids. If lae1 gene along with major hemi-cellualse genes were deleted, the production of sesquiterpenoid ophiobolin F (113) in T. reesei was increased to 1187.06 mg/L by using the modified chassis [120].
Deletion of VmLaeA in apple canker pathogen Valsa mali led to greatly reduced virulence with lesion length reduced by 48% on apple twigs. The toxicity of secondary metabolites produced by VmLaeA deletion mutant (ΔVmlaeA) was markedly decreased in comparison with the wild type strain. Unfortunately, these toxic metabolites have not been identified [121].

3. Regulation of Velvet Proteins on Secondary Metabolite Production in Fungi

The velvet proteins (or called velvet family proteins) included VeA (velvet A), VelB (velvet like B), VelC (velvet like C), VelD (velvet like D) and VosA (viability of spores A). These five proteins all contain the velvet and transactivation domains. They are highly conserved in dimorphic and filamentous fungi [40,124,125,126]. They mainly play important roles in fungal development, asexual sporulation, sexual development, secondary metabolism, and stress tolerance [127]. It has been revealed that LaeA and velvet proteins formed the multimeric complexes such as VelB-VeA-LaeA, VelB-VosA, and VelB-VelB in fungi. The heterotrimeric VelB-VeA-LaeA complex controls sexual development and secondary metabolism in response to light [128,129,130,131,132]. The following is the research progress of velvet proteins on the regulation of secondary metabolite production in fungi.

3.1. Regulation of VeA on Secondary Metabolite Production in Fungi

The VeA (also called VelA, Ve1, and Vel1) proteins usually positively regulated production of secondary metabolites in fungi. Most of the regulated metabolites were polyketides. Some examples of VeA regulating secondary metabolite production in fungi are shown in Table 2. The structures of the metabolites are shown in Figure S1.
Disruption of the AcveA gene in Acremonium chrysogenum resulted in reduction of cephalosporin C (114) production, which meant AcVeA positively regulated cephalosporin C (114) biosynthesis in A. chrysogenum [133].
Deletion of veA gene in Alternaria alternata greatly reduced sporulation and production of alternariol (AOH, 4) and alternariol monomethyl ether (AME, 5) [27]. The production of both AOH (4) and AME (5) in A. alternata was significantly stimulated by blue light. The disruption of AaVeA resulted in a marked decrease of AOH (4) and AME (5) production under blue light illumination [134].
Aspergillus carbonarius was the pathogen of grape Aspergillus rot [135]. The fungus could produce ochratoxin A (OTA, 10). Deletion of veA in A. carbonarius, the production of OTA (10) was almost disappeared [34]. Deletion of veA in A. carbonarius resulted in significant reduction of OTA (10) production. During both in vitro growth and infection of grapes, non-mycotoxigenic strains could outcompete the wild-type strain. OTA (10) defective ΔveA mutant was considered as the potential biocontrol agent [136].
VeA affected the biosynthesis of mycotoxins in Aspergillus flavus. Deletion of veA in A. flavus decreased the production of cyclopiazonic acid (18), aflatrem B (115), and aflatoxins [137]. Deletion of veA also decreased the production of asparasone A (116) [138] and aflatoxin B1 (17) in A. flavus [139]. VepN contained a septin-type guanine nucleotide-binding domain, representing a conserved protein family from yeast to humans belonging to the P-loop GTPase superfamily. It was found that the global regulation gene veA positively regulated vepN to influence aflatoxin production, morphological development, and pathogenicity in A. flavus [140].
Both deletion and overexpression of veA in Aspergillus fumigatus led to decreased production of gliotoxin (21). The RNA sequencing data provided evidence supporting this pattern. It was possible that both deletion and over-expression of veA downregulated fumR transcription, suggesting that veA influences the activation of the fumagillin gene cluster through regulation of fumR [141]. The similar regulation pattern was also observed in A. fumigatus to produce other secondary metabolites. Both deletion and overexpression of veA in A. fumigatus decreased production of fumagillin (23), gumitremorgin G (117), fumigaclavine C (118) and glionitrin A (119) [142].
The deletion of veA in A. nidulans suppressed the production of sterigmatocystin (16). The veA deletion mutant produced less penicillin G (28) than the regular strain. The veA gene was also required for sexual development [143]. The deletion of veA gene in A. nidulans reduced productin of sterigmatocystin (16) and norsolorinic aid (NOR, 27) [54]. VeA was thought to be involed in the penicillin G (28) biosynthesis via repression of the expression of acvA gene, which led to reduced penicillin production in A. nidulans [144]. Further investigaton was that VeA repressed the expression of cryptic orsellinic acid (120) BGC in A. nidulans through histone 3 acetylation. Deletion of veA led to increased production of orsellinic acid (120), F9775A (121) and F9775B (122) in A. nidulans [145]. Further investigation revealed that A. nidulans VeA was a multi-phosphorylated protein and hypothesized that at least four specific amino acids (T167, T170, S183 and Y254) underwent reversible phosphorylation to trigger development and sterigmatocystin (16) biosynthesis. Double mutation of T167 to valine and T170 to glutamic acid exerted the largest effects with regards to sexual development and veA gene expression [146]. In the dark, VeA entered the nucleus of A. nidulans, formed VelB-VeA-LaeA heterotrimeric complex, and controlled sexual development and enhanced sterigmatocystin (16) production [128]. The downstream transcription factor regulatory gene of veA was revealed as mtfA in A.nidulans. Deletion of mtfA could decrease the expression of the genes in the penicillin gene cluster, reducing penicillin production. In this case, overexpression of mtfA enhanced the transcription of penicillin BGC, increasing penicillin production more than 5 fold with respect to the control. However, it was detrimental for the expression of terrequinone BGC either deletion or overexpression of mtfA. In addition to its effect on secondary metabolism, mtfA also affected asexual and sexual development in A. nidulans. Deletion of mtfA resulted in a reduction of conidiation and sexual stage [147]. Another example about downstream transcription factor regulatory gene of veA1 was revealed as sclB in A. nidulans. Deletion of sclB also decreased production of aspernidines [148].
The deletion of veA in Aspergillus niger suppressed the production of ochratoxins A (OTA, 10), α (OTα, 123) and β (OTβ, 124). The veA gene acted as the positive regulator of conidia production, OTA (10) biosynthesis, and oxidative stress tolerance in A. niger, regardless of light conditions. Darkness promoted conidial production and OTA (10) biosynthesis in the wild-type strain of A. niger [149]. The deletion of veA in A. oryzae also decreased production of kojic acid (20) [150]. Disruption of veA significantly reduced the production of echinocandin B (39) and sterigmatocystin (16) in A. pachycristatus [65]. Deletion of veA gene in A. parasiticus reduced aflatoxin BGC gene expression and aflatoxisome development [151].
CgVeA in Chaetomium globosum was thought of as a light signaling responsive regulator. It was involved in regulation of chaetoglobusin A (48) biosynthesis. Deletion of CgveA caused an obvious decrease in chaetoglobusin A (48) production from 51.32 to 19.76 mg/L under dark condition. In contrast, CgveA overexpression resulted in a dramatic increase in chaetoglobusin A (48) production, reaching 206.59 mg/L under illumination, which was higher than that noted in darkness. The RT-qPCR results confirmed that CgVeA, as a light responsive regulator, positively regulated chaetoglobusin A (48) biosynthesis by controlling the expression of core genes of the chaetoglobusin A (48) biosynthetic gene cluster and other relevant regulators [152].
Deletion of veA in tomato fungal pathogen Cladosporium fulvum led to increased production of the pigment cladofulvin (55), which meant that VeA negatively regulated biosynthesis of cladofulvin (55) in this fungus [76].
Deletion of veA in Fusarium fujikuroi led to decreased production of gibberellins A3 (63) and A4 (64), fusarin C (65), fumonisins B1 (66), B2 (67), B3 (68) and B4 (69), deoxynivalenol (70), and 15-acetyl deoxynivalenol (71). However, the production of bikaverin (61) was increased in the deletion mutant [83]. The similar results were confirmed later. Deletion of vel1 led to reduced production of fusaric acid (62), fusarinolic acid (72), and dehydrofusaric acid (73) in F. fujikuroi strain [84]. Deletion of vel1 led to decreased production of gibberellins, fumonisins and fusarin C (65). Overexpression of lae1 led to increased production of gibberelins in another F. fujikuroi strain [85]. Deletion of vel1 gene in F. fujikuroi led to upregulation of gibepyrone BGC expression as well as increased production of gibepyrones A (74), B (75), C (76), D (77), E (78), and F (79) [86].
Deletion of veA in Fusarium graminearium, the causal agent of Fusarium head blight, led to reduced production of deoxynivalenol (vomintoxin or DON, 68) [153], and also led to decreased production of trichothecenes [154].
Overexpression of FnveA in Fusarium nematophilum, the antitumor activity of the crude extract was increased on A549 cancer cells. Unfortunately, the antitumor compounds were not identified [155].
Deletion of veA in Fusairum oxysporum caused the decreased production of beauvericin (44) and fusaric acid (62), which contributed to virulence on plant hosts such as tomato plants [88]. Deletion of FoVel1 gene in F. oxysporum f.sp. niveum led to depressed conidiation and reduced production of bikaverin (61) and fusaric acid (62). In addition, all of these alterations in the deleted mutants were restored in the corresponding complementation strains. [89].
Deletion of Ffvel1 in Fusarium verticillinoides led to decreased production of gibberellins (63) and A4 (64), fusarin C (65), fumonisins B1 (66), B2 (67), B3 (68) and B4 (69), deoxynivalenol (70), and 15-acetyl deoxynivalenol (71). However, the production of bikaverin (61) was increased in the deletion mutant. The regulation mechanisms of vel1 on the above metabolite production should be similar to those of laeA in this fungus [83]. Deletion of veA in maize pathogen Fusarium verticillioides led to decreased production of fusarin C (65), fumonisins B1 (66), B2 (67) and B3 (68) [156]. Further investigation showed that VeA was necessary for causing symptom and mycotoxin synthesis in maize seedlings by F. verticillioides [157].
Deletion of mve1 gene in Mycosphaerella graminicola decreased production of melanin. The Δmve1 mutant displayed albino phenotype with significant reduction in melanin biosynthesis and less production of aerial mycelia on agar plates [158].
Deletion of veA gene in Neurosopora crassa decreased both asexual conidiation and carotenoid production [159]. Further investigation showed that the production of siderophore coprogen (125) was also decreased in ΔveA mutant of N. crassa [160].
Deletion of veA gene in Penicillium chrysogenum decreased the production of penicillin G (28) [101,161]. Small reduction of penicillin G (28) was also reported in another ΔPcvelA mutant of P. chrysogenum [103]. P. citrinum is well-known to produce compactin (also called ML-236B or mevastatin, 98). This polyketide exhibited a potent inhibitory activity on 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Compactin (98) was industrially converted into pravastatin by microbes. Currently, pravastatin has been widely used as a pharmaceutical drug for the treatment of hypercholesterolemia [161]. Deletion of veA in P. citrinum led to suppressed production of compactin (98), and overexpression of veA led to increased production of compactin (98). It indicated that veA is the key regulation factor of compactin (98) biosynthesis [105]. Overexpression of veA in P. citrinnum led to the compactin (98) production to be increased [162].
Penicillium expansum is the causal agent of apple blue mould disease [163]. It produces the mycotoxins citrinin (81) and patulin (105). The disruption of veA in P. expansum drastically reduced the production of citrinin (81) and patulin (105) on synthetic media, associated with a marked down-regulation of all genes involved in the biosynthesis of the two mycotoxins. Moreover, the null mutant ΔPeveA strain was unable to produce patulin (105) on apples [127]. Deletion of veA in P. expansum led to the production of patulin (105) in ΔveA mutant to be completely blocked [164,165]. The ΔveA mutants also exhibited reduced growth and conidiation when exposed to stressors, including cell membrane stress, oxidative stress, osmotic stress, and different pH values, which indicated that patulin (105) contributed to fungal anti-stress ability. Non-mycotoxigenic strain ΔveA of P. expansum showed its biocontrol capability against postharvest pathogen of pome fruit during postharvest handling and storage [165].
Deletion of veA gene in Pestalotiopsis microspora led to increased production of pestalotiollide B (103). The veA gene appeared to negatively regulate the biosynthesis of pestalotiollide B (103) [115].

3.2. Regulation of VelB on Secondary Metabolite Production in Fungi

VelB (also called Vel2) mainly coordinates with other members such as LaeA, VeA and VosA to regulate the production of fungal secondary metabolites in fungi as VelB lacked the site of nuclear localization signal (NLS) [128]. Some examples of VelB regulating secondary metabolite production in fungi are shown in Table 3. The structures of the metabolites are shown in Figure S1.
Deletion of velB in Aspergillus flavus abolished aflatoxin production and sclerotial formation either under illumination or in darkness. VelB may have a dual role and likely coordinate with FluG to modulate its functions [167]. Similar result was reported by Eom et al. that inactivation of velB led to decreased production of aflatoxin B1 (17) in A. flavus [139].
Knock out of velB gene in Aspergillus nidulans led to reduced content of sterigmatocystin (16) under illumination. However, the production yield of sterigmatocystin (16) in deletion mutant was almost the same as that of wild type strain, which indicated that the mycelial growth rate of deletion mutant was bigger than that of wild type strain [128]. Further investigation showed that the deletion of velB in A. nidulans resulted in decreased mRNA levels of vadJ throughout the life cycle. Conversely, the deletion of vadJ resulted in elevated production of sexual fruiting bodies and sterigmatocystin (16). This indicated that velB was necessary for proper coordination via vadJ to regulate sterigmatocystin (16) production [168].
Deletion of velB gene in Aspergillus ochraceus led to drastically reduced production of ochratoxin A (OTA, 10) [61].
The deletion of BcvelB led to increased conidiation and melanin biosynthesis in Botrytis cinerea. Expression of melanin biosynthesis gene cluster was also up-regulated [169].
CsVelB positively regulated melanin production of Colletotrichum siamense [170].
Deletion of ClvelB gene in Curvularia lunata led to the decrease of the production of conidia and the phytotoxin methyl 5-hydroxymethylfuran-2-carboxylate (126). The ΔClvelB mutant was impaired in colonizing the host tissue. However, deletion of ClvelB gene led to the increase in aerial hyphae and melanin production [171].
Deletion of vel2 gene in F. fujikuroi led to upregulation of gibepyrone BGC expression as well as increased production of gibepyrones A (74), B (75), C (76), D (77), E (78), and F (79) [86].
Deletion of FgvelB in Fusarium graminearum led to decreased production of deoxynivalenol (DON, 68) [172]. Production of trichothecenes and zearalenone (80) in FgvelB-deleted strain of F. graminearum was also dramatically reduced compared with the wild strain [173]. A similar example is that the deletion of FpvelB led to notable differences in growth, conidiation, virulence and deoxynivalenol (68) production in F. pseudograminearum. Furthermore, FpVelB positively regulated another secondary metabolite BGC associated with pathogenesis by modulating the expression of the PKS11 gene. FpVelB regulated pathogen virulence by influencing deoxynivalenol (68) production in F. pseudograminearum [174].
Deletion of velB in Neurospora crassa led to reduced biosynthesis of light-dependent carotenoids [160].
Penicillium expansum is the pathogen of apple blue mold disease and the main producer of patulin (105). The ΔPevelB mutant colonized apples, but at a lower rate than the wild type and complemented strains. Conidiation was significantly reduced in theΔPevelB strain. Under light conditions, the ΔPevelB strain showed a reduced level of spore viability. Deletion of the velB gene strongly inhibited the production of mycotoxins chaetoglobusin A (48), citrinin (81), and patulin (105) on synthetic media or in planta, but increased the production of fumarylalanine (127). In addition, the genes involved in siderophore biosynthesis, ergosterol biosynthesis, and nitrate assimilation were also upregulated in the ΔPevelB strain. This indicated that VelB was involved in the development, pathogenicity, and secondary metabolism of P. expansum [175].
Deletion of veA in Pestalotiopsis microspora led to a decrease in production of pestalotiollide B (103). The velB gene appeared to stimulate the biosynthesis of pestalotiollide B (103) [115].

3.3. Regulation of VelC, VelD and VosA on Secondary Metabolite Production in Fungi

In velvet proteins, the functions of VelC, VelD and VosA in fungi have been seldom studied for their regulation on secondary metabolism. Some examples of VelC, VelD and VosA regulating secondary metabolite production in fungal species of the genera Aspergillus and Penicillium are shown in Table 4. The structures of the metabolites are shown in Figure S1.

3.3.1. Regulation of VelC

The VelC (also called Vel3 and VE-3) protein belongs to the velvet family of regulators involved in the control of development and secondary metabolite production in fungi [177]. Deletion of velC gene in Aspergillus oryzae led to decreased production of kojic acid (20) [150]. Deletion of velC gene in Penicillium expansum led to markedly decreased production of patulin (105) [164]. For the above two fungal species, VelC positively regulated secondary metabolite production.

3.3.2. Regulation of VelD

The VelD protein was also called Vel4. Deletion of velD gene in Aspergillus flavus led to decreased production of aflatoxin B1 (17) [139]. Another example was that deletion of velD gene in A. oryzae led to decreased production of kojic acid (20) [150]. It indicated that VelD positively regulated secondary metabolite production in A. flavus and A. oryzae.

3.3.3. Regulation of VosA

The regulation of VosA on secondary metabolite production was studied in detail in Aspergillus nidulans. The deletion of vosA in A. nidulans resulted in the lack of trehalose (128) in spores, a rapid loss of the cytoplasm, organelles and viability of spores, and a dramatic reduction in tolerance of conidia to heat and oxidative stress [178]. RNA-seq-based genome-wide expression analysis demonstrated that the loss of vosA in A. nidulans led to elevated expression of sterigmatocystin (16) biosynthetic genes and a slight increase in sterigmatocystin (16) production in ascospores. Moreover, the deletion of vosA caused upregulation of additional gene clusters associated with the biosynthesis of other secondary metabolites including asperthecin (129), microperfuranone (130), and monodictyphenone (131) [179]. VosA in A. nidulans could interact with the downstream target SclB to negatively regulated production of secondary metabolites including emericellamides A (132), C (133) and D (134), austinol (135) and dehydroaustinol (136) [125]. The second instance was that VosA-repressed dnjA gene negatively regulated metabolism in Aspergillus species. The deletion of dnjA caused increased production of sterigmatocystin (16) and aflatoxin B1 (17) in A. nidulans and A. flavus, respectively [180]. The third instance was that the VosA-VelB-repressed mcrA gene negatively regulated sterigmatocystin (16) production in A. nidulans. The conidia of ΔmcrA mutant contained more amounts of sterigmatocystin (16) [181]. The fourth instance was that VosA-VelB targeted gene vidD, which was required for proper fungal growth, development, and sterigmatocystin (16) production in Aspergillus nidulans [182]. Furthermore, transcriptomic, protein-DNA interaction, and metabolomics studies of VosA, VelB and WetA in A. nidulans played interdendent, overlapping, and distinct roles in governing morphological development and metabolic remodeling in the conida, leading to the production of vital conidia suitable for fungal proliferation and dissemination. The related secondary metabolites regulated by VosA, VelB and WetA in A. nidulans asexual spores included sterigmatocystin (16), austinol (135), dehydroaustinol (136), norsolorinic acid (137), nidurufin (138), versiconol (139), and emericellamids A (132), C (133), D (134), E (140), and F (141) [183]. In addition, Vos-VelB could activate putative C6 transcription factor VadZ to regulate development and sterigmatocystin (16) production in A. nidulans [184].

4. Conclusions

LaeA and velvet proteins could obviously regulate the production of fungal secondary metabolites by responding to the light conditions under which fungi are grown. We can manipulate fungal secondary metabolite production to inhibit the production of harmful mycotoxins while promoting the production of useful metabolites [160]. However, we only know a little about the regulation mechanisms between LaeA/velvet proteins and secondary metabolite BGC expression, which should be studied in detail in the future [11,14,70,185].
In summary, it should be an effective strategy to promote or inhibit production of secondary metabolites through global regulation of LaeA and velvet proteins in fungi. Some cryptic BGCs for secondary metabolite production are possibly activated by LaeA and velvet proteins through the regulatory networks. It is beneficial for the excavation of bioactive compounds from fungi. Furthermore, some non-mycotoxigenic fungal strains obtained by deletion or overexpression of laeA or velvet protein encoding genes could be used as the biocontrol agents by applying in plants to reduce mycotoxin contamination [165].

Supplementary Materials

The following supporting information can be downloaded at the website of this paper posted on Preprints.org, Figure S1: Structures of the compounds 1–141 identified from fungi through regulation of LaeA and velvet proteins.

Author Contributions

Conceptualization, L.Z.; writing—original draft preparation, X.H. and L.Z.; writing—review and editing, D.X. and D.L.; visualization, X.H. and L.L.; funding acquisition, L.Z.; All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (32072373 and 31471729).

Data Availability Satement

Not applicable..

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

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Table 1. Some examples of LaeA regulating secondary metabolite production in fungi.
Table 1. Some examples of LaeA regulating secondary metabolite production in fungi.
Fungus Overexpression/
Deletion of laeA 		Positive/Negative
Regulation		 Production of Secondary Metabolites Ref.
Alternaria
alstroemeria 		Overexpression Positive Increased production of myricetin (1), geraniol (2), ergosterol (3) and other compounds determined by metobolomic analysis. [24]
Alternaria
alstroemeria 		Overexpression Negative Decreased production of the antitumor compounds via controlling the transcription of AaFla1. [25]
Alternaria
alternata 		Deletion Positive Decreased production of alternariol (4) and alternariol monomethyl ether (5). [27]
Alternaria
alternata 		Overexpression Positive Increased production of the anti-inflammatory meroterpenoid tricycloalternarene O (6). [28]
Arthrobotrys
flagrans 		Overexpression and deletion Positive Increased production of the secondary metabolites by overexpression of AflaeA, and decreased production of the secondary metabolites by deletion of AflaeA. [29]
Aspergillus sp. Z5 Overexpression Positive Increased production of diorcinol (7). [30]
Aspergillus sp. FKI-5362 Overexpression Positive Increased production of MS-347a (8). [31]
Aspergillus
carbonarius 		Deletion Positive Decreased production of citric acid (9). [33]
Aspergillus
carbonarius 		Deletion Positive Decreased production of ochratoxin A (10). [34]
Aspergillus
carbonarius 		Deletion Positive Decreased production of ochratoxin A (10) in ΔlaeA strain colonized in nectarines and grapes. [35]
Aspergillus
carbonarius 		Inhibtion of LaeA Positive Decreased production of ochratoxin A (10) by treatment with eugenol through inhibiting LaeA expression [36]
Aspergillus
cristatus 		Overexpression Positive Increased production of multiple secondary metabolites including terpenoids and flavonoids. [37]
Aspergillus flavipes Deletion Negative Increased production of flavipamides A (11) and B (12), asperphenamate (13), 4′-OMe-asperphenamate (14), and cyclic Pro-Gly-Val-Gly-Try(8-OH, 3-prenyl)-Gly-Trp (15). [38]
Aspergillus
flavus 		Deletion Positive Decreased production of sterigmatocystin (16). [43]
Aspergillus
flavus 		Deletion Positive Decrease production of aflatoxins. [39]
Aspergillus
flavus 		Deletion Positive Decreased production of aflatoxin B1 (17). [40]
Aspergillus
flavus 		Deletion Positive Decreased production of aflatoxins. [41]
Aspergillus
flavus 		Deletion Positive Decreased production of aflatoxins, cyclopiazonic acid (18) and ustiloxin B (19). [44]
Aspergillus
flavus 		Deletion Positive Decreased production of aflatoxins. [42]
Aspergillus
flavus 		Deletion Positive Decreased production of aflatoxins and kojic acid (20). [45]
Aspergillus
fumigatus 		Deletion Positive Decreased production of gliotoxin (21) and endocrocin (22). [43]
Aspergillus
fumigatus 		Deletion Positive Decreased production of several mycotoxins including gliotoxin (21). [46]
Aspergillus
fumigatus 		Deletion Positive Decreased production of gliotoxin (21), fumagillin (23), fumagatin (24) and helvolic acid (25). [47]
Aspergillus
fumigatus 		Deletion Positive Decreased production of gliotoxin (21). [48]
Aspergillus
fumigatus 		Deletion Positive Decreased production of endocrocin (22) [49]
Aspergillus
fumisynnematus 		Overexpression Positive Increased production of cyclopiazonic acid (18). [50]
Aspergillus
luchuensis mut. kawachii 		Deletion Positive Decreased production of citric acid (9). [51]
Aspergillus
nidulans 		Overexpression Positive Increased production of terrequinone A (26). [53]
Aspergillus
nidulans 		Deletion Positive Decreased production of sterigmatocystin (16) and norsolorinic aid (27). [54]
Aspergillus
nidulans 		Deletion Positive Decreased production of streigmatocystin (16) and penicillin G (28). [43]
Aspergillus
nidulans 		Deletion Positive Depressed expression of genes involved in biosynthesis of sterigmatocystin (16), terrequinone A (26) and penicillin G (28). [55]
Aspergillus
nidulans 		Deletion Negative Increased production of sterigmatocystin (16). [56]
Aspergillus
nidulans 		Overexpression Positive Increased production of sterigmatocystin (16). [52]
Aspergillus
niger 		Deletion Positive Decreased production of asperrubrol (29), atromentin (30) and JBIR 86 (31). [58]
Aspergillus
niger 		Deletion Negative Increased production of aspernigrin A (32) and BMS-192548 (33). [58]
Aspergillus
niger 		Overexpression Positive Increased production of flaviolin (34), orlandin (35) and kotanin (36). [59]
Aspergillus
niger 		Overexpression and deletion Positive Decreased production of OTA (10) in the deleted mutant, but increased production of OTA (10) in the overexpressed mutant. [62]
Aspergillus
ochraceus 		Deletion Positive Decreased production of OTA (10). [61]
Aspergillus
oryzae 		Deletion Negative Increased production of kojic acid (20). [63]
Aspergillus
oryzae 		Overexpression Positive Increased production of monacolin K (37) and terrequinone A (38) [64]
Aspergillus
pachycristatus 		Deletion Positive Decreased production of sterigmatocystin (16) and echinocandin B (39). [65]
Aspergillus
pseudoterreus 		Overexpression Positive Increased production of itaconic acid (40). [66]
Aspergillus terreus Overexpression Positive Increased production of lovastatin (41). [67]
Aspergillus terreus Overexpression Positive Increased production of dihydroisoflavipucines 1 (42) and 2 (43). [70]
Beauveria
bassiana 		Overexpression and deletion Positive Decreased production of beauvericin (44) and bassiatin (45) in the BbLaeA disruption strain, but increased production in the overexpressed strain. [71]
Botrytis
cinerea 		Deletion Positive Decreased production of oxalic acid (46). [72]
Botrytis
cinerea 		Deletion Positive Decreased production of abscisic acid (47). [73]
Chaetomium
globosum 		Overexpression Positive Increased production of seven cytochalasans including chaetoglobosins A (48), B (49), D (50), E (51), O (52), V (53) and Z (54). [74]
Chaetomium
globosum 		Overexpression and deletion Positive Decreased production of chaetoglobusin A (48) in ΔCglaeA mutant, restored production of chaetoglobusin A (48) in CglaeA-C strain, and increased production of chaetoglobusin A (48) in CglaeA-OE strain. [75]
Cladosporium
fulvum 		Deletion Negative Increased production of cladofulvin (55). [76]
Cochliobolus
heterostrophus 		Deletion Positive Decreased production of T-toxin (56). [77]
Coprinopsis
cinerea 		Deletion Negative Increased production of coprinoferrin (57). [78]
Daldinia
eschscholzii 		Replacement of a strong pgdA promoter Positive Induced production of dalestones A (58) and B (59) [80]
Dothistroma
septosporum 		Deletion Negative Increased production of dothistromin (60). [81]
Fusarium
fujikuroi 		Deletion Negative Increased production of bikaverin (61). [83]
Fusarium
fujikuroi 		Deletion Positive Decreased production of gibberellins A3 (63) and A4 (64), fusarin C (65), fumonisins B1 (66), B2 (67), B3 (68) and B4 (69), deoxynivalenol (70), and 15-acetyl deoxynivalenol (71). [83]
Fusarium
fujikuroi 		Deletion Positive Decreased production of fusaric acid (62), fusarinolic acid (72), and dehydrofusaric acid (73) [84]
Fusarium
fujikuroi 		Deletion and overexpression Positive Deletion of laeA led to decreased production of gibberellins, fumonisins and fusarin C (65). Overexpression of laeA led to increased production of gibberelins. [85]
Fusarium
fujikuroi 		Deletion Negative Increased production of gibepyrones A (74), B (75), C (76), D (77), E (78), and F (79) [86]
Fusarium
graminearum 		Deletion and overexpression Positive Deletion of FglaeA led to a dramatic reduced production of trichothecenes and zearalenone (80). Overexpression of FglaeA caused the increased production of trichothecenes and zearlenone (80). [87]
Fusarium
oxysporum 		Deletion Positive Decreased production of beauvericin (44) and fusaric acid (62) [88]
Fusarium oxysporum f.sp. niveum Deletion Positive Decreased production of bikaverin (61) and fusaric acid (62) [89]
Fusarium
verticillioides 		Deletion Positive Decreased production of bikaverin (61), fusaric acid (62), fusarin C (65) and fumonisins. [90]
Ganoderma
lingzhi 		Deletion and overexpression Positive Decreased production of ganoderic acids in the deleted mutant, and increased ganoderic acids in the overexpressed mutant. [92]
Magnaporthe
oryzae 		Overexpression Positive Decreased production of melanin, and increased production penicillin G (28) [93]
Magnaporthe
oryzae 		Overexpression Positive Increased production of secondary metabolites. [94]
Monascus
pilosus 		Overexpression Positive Increased production of monacolin K (37) and unidentified pigments. [96]
Monascus
purpureus 		Overexpression Positive Increased production of monacolin K (37). [97]
Monascus
ruber 		Deletion Positive Decreased production of citrinin (81) and six pigments rubropunctamine (82), monascorubramine (83), monascin (84), rubropunctatin (85), ankaflavin (86), and monascorubrin (87). [98]
Penicillium sp. LC1-4 Overexpression Positive Increased production of quinolactacin A (88). [30]
Penicillium sp. MB Deletion Positive Inhibited production of the members with the 1-oxa-7-aza-spiro[4,4] non-2-ene-4,6-dione skeleton, including pseurotins A (89), B (90), C (91), D (92), and E (93). [99]
Penicillium brocae HDN-12-143 Overexpression Positive Increased production of fumigatin chlorohydrin (94), iso-fumitatin chlorohydrin (95), spinulosin (96) and pyranonigrin F (97) [100]
Penicillium
chrysogenum 		Overexpression and deletion Positive Overexpression of PclaeA gene led to increased production of penicillin G (28). Deletion of PclaeA led to decreased production of penicillin G (28). [22]
Penicillium
chrysogenum 		Deletion Positive Decreased production of penicillin G (28). [101]
Penicillium
chrysogenum 		Deletion Positive Decreased production of penicillin G (28). [102]
Penicillium
chrysogenum 		Deletion Positive Small reduction of penicillin G (28) [103]
Penicillium
citrinum 		Deletion Positive Decreased production of compactin (98). [105]
Penicillium
digitatum 		Deletion Positive Reduced expression of several secondary metabolite BGCs. [106]
Penicillium dipodomyis YJ-11 Overexpression Positive Increased production of sorbicillinoids including 10,11-dihydrobislongiquinolide (99), 10,11,16,17-tetrahydrobislongiquinolide (100), bislongiquinolide (101), 16,17-dihydrobislongiquinolide (102), sohirnone A (103), and 2’,3’-dihydrosorbicillin (104). [109]
Penicillium
expansum 		Deletion Positive Decreased production of patulin (105). [110,111]
Penicillium
oxalicum 		Deletion Positive Decreased production of secondary metabolites. [112]
Penicillium
oxalicum 		Deletion Positive Four of the 28 secondary metabolite BGCs were significantly downregulated. [113]
Penicillium
roqueforti 		Deletion Positive Decreased production of roquefortine C (106), mycophenolic acid (107), and andrastin A (108). [114]
Pestalotiopsis
microspore 		Deletion Positive Decreased production of pestalotiollide B (109). [115]
Pleurotus
ostreatus 		Deletion Positive Decreased production of the intracellular polysaccharide (IPS). [116]
Pyricularia oryzae Deletion and overexpression Positive Deletion of PoLAE1 reduced the production of tenuazonic acid (110). Overexpression of PoLAE1 led to increased production of tenuazonic acid (110). [117]
Trichoderma
afroharzianum 		Overexpression Positive Induced production of (1R,3E,5E)-1-(3,5-dihydroxy- 2,4-dimethylphenyl)-1-hydroxyhepta- 3,5-dien-2-one (111) and (1R,3E,5E)-1-(3,5-dihydroxy- 2,4-dimethylphenyl)-1-methoxyhepta- 3,5-dien-2-one (112). [118]
Trichoderma
longibrachiatum 		Deletion and overexpression Positive Deletion of Tllae1 reduced the production of peptaibols. Overexpression of Tllae1 led to 2-fold increased production of petaibols. [122]
Trichoderma
reesei 		Overexpression Positive Increased production of sorbicillinoids. [123]
Trichoderma
reesei 		Deletion Positive Decreased production of sterigmatocystin (16). [119]
Trichoderma
reesei 		Deletion Negative Increased production of ophiobolin F (113) [120]
Valsa mali Deletion Positive Decreased production of toxic metabolites. [121]
Table 2. Some examples of VeA regulating secondary metabolite production in fungi.
Table 2. Some examples of VeA regulating secondary metabolite production in fungi.
Fungus Overexpression/
Deletion of veA 		Positive/Negative
Regulation		 Production of Secondary Metabolites Ref.
Acremonium
chrysogenum 		Deletion Positive Decreased production of cephalosporin C (114). [133]
Alternaria
alternata 		Deletion Positive Decreased production of alternariol (4) and alternariol monomethyl ether (5). [27]
Alternaria
alternata 		Deletion Positive Decreased production of alternariol (4) and alternariol monomethyl ether (5). [134]
Aspergillus
carbonarius 		Deletion Positive Production of ochratoxin A (10) was decreased to almost zero. [34]
Aspergillus
carbonarius 		Deletion Positive Decreased production of ochratoxin A (10). [136]
Aspergillus
flavus 		Deletion Positive Decreased production of cyclopiazonic acid (18), aflatrem B (115), and aflatoxins. [137]
Aspergillus
flavus 		Deletion Positive Decreased production of asparasone A (116). [138]
Aspergillus
flavus 		Deletion Positive Decreased production of aflatoxin B1 (17). [139]
Aspergillus
flavus 		Deletion and overexpression Positive Decreased production of aflatoxins in deletion muatant, and increased production of aflatoxins in overexpression mutant. [140]
Aspergillus
fumigatus 		Deletion Positive Decreased production of gliotoxin (21). [141]
Aspergillus
fumigatus 		Overexpression Negative Decreased production of gliotoxin (21). [141]
Aspergillus
fumigatus 		Deletion Positive Decreased production of fumagillin (23), gumitremorgin G (117), fumigaclavine C (118) and glionitrin A (119). [142]
Aspergillus
fumigatus 		Overexpression Negative Decreased production of fumagillin (23), gumitremorgin G (117), fumigaclavine C (118) and glionitrin A (119). [142]
Aspergillus
nidulans 		Deletion Positive Decreased production of sterigmatocystin (16) and penicillin G (28). [143]
Aspergillus
nidulans 		Deletion Positive Decreased production of penicillin G (28). [144]
Aspergillus
nidulans 		Deletion Positive Decreased production of sterigmatocystin (16) and norsolorinic aid (27) [54]
Aspergillus
nidulans 		Deletion Negative Increased production of orsellinic acid (120), F9775A (121) and F9775B (122). [145]
Aspergillus
nidulans 		Deletion Positive Decreased production of aspernidines [148]
Aspergillus
niger 		Deletion Positive Decreased production of ochratoxins A (10), α (123) and β (124). [149]
Aspergillus
ochraceus 		Deletion Positive Decreased production of ochratoxin A (10). [61]
Aspergillus
oryzae 		Deletion Positive Decreased production of kojic acid (20). [150]
Aspergillus
pachycristatus 		Deletion Positive Decreased production of sterigmatocystin (16) and echinocandin B (39). [65]
Aspergillus
parasiticus 		Deletion Positive Decreased production of sterigmatocystin (16). [166]
Aspergillus
parasiticus 		Deletion Positive Reduced aflatoxin BGC gene expression and aflatoxisome development [151]
Chaetomium
globosum 		Deletion and overexpression Positive Decreased production of chaetoglobusin A (48) in veA deleted mutant, and increased production of chaetoglobusin A (48) in veA overexpressed mutant. [152]
Cladosporium
fulvum 		Deletion Negative Increased production of cladofulvin (55). [76]
Cochliobolus
heterostrophus 		Deletion Positive Decreased production of T-toxin (56). [77]
Fusarium
fujikuroi 		Deletion Negative Increased production of bikaverin (61). [83]
Fusarium
fujikuroi 		Deletion Positive Decreased production of gibberellins A3 (63) and A4 (64), fusarin C (65), fumonisins B1 (66), B2 (67), B3 (68) and B4 (69), deoxynivalenol (70), and 15-acetyl deoxynivalenol (71). [83]
Fusarium
fujikuroi 		Deletion Positive Decreased production of fusaric acid (62), fusarinolic acid (72), and dehydrofusaric acid (73) [84]
Fusarium
fujikuroi 		Deletion Positive Decreased production of gibberellins, fumonisins and fusarin C (65). [85]
Fusarium
fujikuroi 		Deletion Negative Increased production of gibepyrones A (74), B (75), C (76), D (77), E (78), and F (79) [86]
Fusarium
graminearium 		Deletion Positive Reduced production of deoxynivalenol (69). [153]
Fusarium
graminearium 		Deletion Positive Decreased production of trichothecenes. [154]
Fusarium
nematophilum 		Overexpression Positive Increased production of antitumor compounds. [155]
Fusarium
oxysporum 		Deletion Positive Decreased production of beauvericin (44) and fusaric aicd (73) [88]
Fusarium oxysporum f.sp. niveum Deletion Positive Decreased production of bikaverin (61) and fusaric acid (62) [89]
Fusarium
verticillioides 		Deletion Positive Decreased production of fusarin C (65) and fumonisins B1 (66), B2 (67) and B3 (68). [156]
Mycosphaerella
graminicola 		Deletion Positive Decreased production of melanin. [158]
Neurospora
crassa 		Deletion Positive Decreased production of carotenoids. [159]
Neurospora
crassa 		Deletion Positive Decreased production of siderophore coprogen (125) and carotenoids. [160]
Penicillium
chrysogenum 		Deletion Positive Decreased production of penicillin G (28). [101]
Penicillium
chrysogenum 		Deletion Positive Decreased production of penicillin G (28). [161]
Penicillium
chrysogenum 		Deletion Positive Small reduction of penicillin G (28) [103]
Penicillium
citrinum 		Deletion and overexpression Positive Decreased production of compactin (98) in the deletion mutant, and increased production of compactin (98) in the overexpressed mutant. [105]
Penicillium
citrinum 		Overexpression Positive Increased production of compactin (98). [162]
Penicillium
expansum 		Deletion Positive Decreased production of citrinin (81) and patulin (105). [127]
Penicillium
expansum 		Deletion Positive Blocked production of patulin (105). [164]
Penicillium
expansum 		Deletion Positive Lost production of patulin (105). [165]
Pestalotiopsis
microspora 		Deletion Negative Increased production of pestalotiollide B (103) [115]
Table 3. Some examples of VelB regulating secondary metabolite production in fungi.
Table 3. Some examples of VelB regulating secondary metabolite production in fungi.
Fungus Overexpression/
Deletion of velB 		Positive/Negative
Regulation		 Production of Secondary Metabolites Ref.
Aspergillus
flavus 		Deletion Positive Decreased production of aflatoxins. [167]
Aspergillus
flavus 		Deletion Positive Decreased production of aflatoxin B1 (17). [139]
Aspergillus
nidulans 		Deletion Positive Decreased production of sterigmatocystin (16). [128]
Aspergillus
nidulans 		Deletion Negative Increased production of sterigmatocystin (16). [168]
Aspergillus ochraceus Deletion Positive Reduced production of ochratoxin A (10). [61]
Aspergillus
oryzae 		Deletion Negative Increased production of kojic acid (20). [150]
Botrytis
cinerea 		Deletion Negative Increased production of melanin. [169]
Colletotrichum
siamense 		Deletion Positive Decreased production of melanin. [170]
Curvularia
lunata 		Deletion Positive Decreased production of methyl 5-hydroxymethylfuran-2-carboxylate (126). [171
Fusarium
fujikuroi 		Deletion Positive Decreased production of gibberellins, fumonisins and fusarin C (65). [85]
Fusarium
fujikuroi 		Deletion Negative Increased production of gibepyrones A (74), B (75), C (76), D (77), E (78), and F (79) [86]
Fusarium
graminearum 		Deletion Positive Decreased production of deoxynivalenol (68). [172]
Fusarium
graminearum 		Deletion Positive Decreased production of trichothecenes and zearalenone (80). [173]
Fusarium
pseudograminearum 		Deletion Positive Decreased production of deoxynivalenol (68). [174]
Neurospora
crassa 		Deletion Positive Reduced biosynthesis of carotenoids. [160]
Penicillium
chrysogenum 		Deletion Negative Increased production of penicillin G (28). [176]
Penicillium
Expansum 		Deletion Positive Blocked production of patulin (105). [164]
Penicillium
expansum 		Deletion Positive Decreased production of chaetoglobusin A (48), citrinin (81) and patulin (105). [175]
Penicillium
expansum 		Deletion Negative Increased production of fumarylalanine (127). [175]
Pestalotiopsis
microspora 		Deletion Positive Decreased production of pestalotiollide B (103). [115]
Table 4. Some examples of VelC, VelD and Vos A regulating secondary metabolite production in fungi.
Table 4. Some examples of VelC, VelD and Vos A regulating secondary metabolite production in fungi.
Overexpression/
Deletion		 Fungus Positive/Negative
Regulation		 Production of Secondary Metabolites Ref.
Deletion of velC Aspergillus
Oyzae 		Positive Decreased production of kojic acid (20). [150]
Deletion of velC Penicillium
Expansum 		Positive Decreased production of patulin (105). [164]
Deletion of velD Aspergillus
flavus 		Positive Decreased production of aflatoxin B1 (17). [139]
Deletion of velD Aspergillus
oyzae 		Positive Decreased production of kojic acid (20). [150]
Deletion of vosA Aspergillus
nidulans 		Positive Lost production of trehalose (128) in spores. [178]
Deletion of vosA Aspergillus
nidulans 		Negative Slightly increased production of sterigmatocystin (16) in ascospores, and upregulation of the BGCs associated with the biosynthesis of other secondary metabolites, including asperthecin (129), microperfuranone (130), and monodictyphenone (131). [179]
Deletion of vosA Aspergillus
nidulans 		Negative Increased production of emericellamides A (132), C (133) and D (134), austinol (135) and dehydroaustinol (136) [125]
Deletion of vosA Aspergillus
nidulans 		Negative Increaseed production of sterigmatocystin (16). [184]
Deletion of vosA Aspergillus
oyzae 		Negative Increased production of kojic acid (20). [150]
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