Overexpression of an LaeA-like Methyltransferase Upregulates Secondary Metabolite Production in Aspergillus nidulans
Overexpression of an LaeA-like Methyltransferase Upregulates Secondary Metabolite Production in Aspergillus nidulans
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DOI：
10.1021/acschembio.9b00380
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发表时间：
2019-07-01
影响因子：
4
通讯作者：
Oakley, Berl R.
中科院分区：
文献类型：
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作者：
Grau, Michelle F.;Entwistle, Ruth;Oakley, Berl R.
真菌次生代谢物（SMs）包括有医学价值的化合物以及有毒、致癌和/或导致真菌发病的化合物。因此，了解真菌次生代谢的调控是很重要的。McrA是最近发现的一种负向调控真菌次生代谢的转录因子。编码mcrA的基因mcrA （mcrA Delta）的缺失会导致许多SMs的上调，并改变1000多个基因的表达。一个被mcrA缺失强烈上调的基因是llmG，一种被认为与LaeA相关的甲基转移酶，LaeA是次级代谢的主要调节因子。我们在携带野生型mcrA或mcrA Delta的菌株中，通过用强组成启动子取代llmG的启动子，人为地上调了llmG。llmG在各种培养基上的上调导致重要毒素sterigmatocystin和至少六个主要SM途径的化合物的产生增加。因此，llmG是一个主SM调节器。与llmG上调相比，mcrA δ通常会导致更大的SMs上调，这表明mcrA对次级代谢的全部影响涉及llmG以外的基因。然而，mcrA Delta和llmG上调的组合通常比单独的mcrA Delta产生更多的化合物（在一个案例中比对照多460倍）。这一结果表明，与单一策略相比，mcrA的缺失和/或llmG的上调可能与其他策略相结合，从而使SM的产生达到更高的水平。
Fungal secondary metabolites (SMs) include medically valuable compounds as well as compounds that are toxic, carcinogenic, and/or contributors to fungal pathogenesis. It is consequently important to understand the regulation of fungal secondary metabolism. McrA is a recently discovered transcription factor that negatively regulates fungal secondary metabolism. Deletion of mcrA (mcrA Delta), the gene encoding McrA, results in upregulation of many SMs and alters the expression of more than 1000 genes. One gene strongly upregulated by the deletion of mcrA is llmG, a putative methyl transferase related to LaeA, a major regulator of secondary metabolism. We artificially upregulated llmG by replacing its promoter with strong constitutive promoters in strains carrying either wild-type mcrA or mcrA Delta. Upregulation of llmG on various media resulted in increased production of the important toxin sterigmatocystin and compounds from at least six major SM pathways. llmG is, thus, a master SM regulator. mcrA Delta generally resulted in greater upregulation of SMs than upregulation of llmG, indicating that the full effects of mcrA on secondary metabolism involve genes in addition to llmG. However, the combination of mcrA Delta and upregulation of llmG generally resulted in greater compound production than mcrA Delta alone (in one case more than 460 times greater than the control). This result indicates that deletion of mcrA and/or upregulation of llmG can likely be combined with other strategies for eliciting SM production to greater levels than can be obtained with any single strategy.