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The Rim15p homolog RimO mediates starvation response and is required for secondary metabolite production in Aspergillus nidulans

ABSTRACT: Depending on the prevailing environmental, developmental and nutritional conditions Aspergillus nidulans produces different combinations of secondary metabolites (SMs). To activate the biosynthetic gene cluster (BGC) for a given SM global, chromatin-based de-repression must be integrated with pathway-specific induction signals. Here we describe a new global regulator affecting the set of starvation-induced SMs. We found a hitherto uncharacterized putative PAS-domain containing kinase to be upregulated in SM-producing cultures. The predicted protein is highly similar to yeast Rim15 which transmits nutritional and stress signals to downstream effectors involved in chromatin regulation, stress and starvation response. The putative kinase – termed RimO – is required for the transcription of a number of starvation-induced SMs including sterigmatocystin (ST). RimO regulates the pathway-specific transcription factor AflR both at the transcriptional and post-translational level. In the absence of RimO aflR is barely transcribed under SM conditions and the protein is not retained in the nucleus. Genome-wide transcriptional profiling showed that cells lacking rimO fail to correctly respond to carbon and nitrogen starvation and continue to transcribe genes of the basic metabolism to a high level. Conversely, overexpression of the kinase made cells largely insensitive to glucose repression and led to overproduction of several secondary metabolites. We propose a model that positions RimO downstream of PKA being necessary to transmit the starvation signal to downstream targets, including chromatin and transcriptional regulators of SM gene clusters. Additionally, it may also regulate signaling modules required for recognizing the starvation response.

ORGANISM(S): Aspergillus nidulans

PROVIDER: GSE184618 | GEO | 2022/03/01

REPOSITORIES: GEO

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Project description:An outstanding feature of filamentous fungi is their ability to produce a wide variety of small bioactive molecules that contribute to their survival, fitness and pathogenicity. The vast collection of these so-called secondary metabolites (SMs) includes molecules that play a role in virulence, protect fungi from environmental damage, act as toxins or antibiotics that harm host tissues or hinder microbial competitors for food sources. Many of these compounds are used in medical treatment, however, biosynthetic genes for the production of these natural products are arranged in compact clusters that are commonly silent under growth conditions routinely used in laboratories. Consequently, a wide arsenal of yet unknown fungal metabolites is waiting to be discovered. Here we describe the effects of deletion of hosA, one of four classical histone deacetylase (HDACs) genes in Aspergillus nidulans; we show that HosA acts as global regulator of SMs in Aspergillus with converse regulatory effects depending on the metabolite gene cluster examined. Co-inhibition of all classical enzymes by the pan HDAC inhibitor trichostatin A and the analysis of HDAC double mutants indicate that HosA is able to override known regulatory effects of other HDACs such as the class 2 type enzyme HdaA. Chromatin immunoprecipitation analysis revealed a direct correlation between hosA deletion, the acetylation status of H4 and the regulation of SM cluster genes, whereas H3 hyperacetylation could not be detected in all the upregulated SM clusters examined. Our data suggest that HosA has inductive effects on SM production in addition to its classical role as a repressor via deacetylation of histones. Moreover, a genome wide transcriptome analysis revealed that in addition to SMs, expression of several other important protein categories, such as enzymes of the carbohydrate metabolism or proteins involved in disease, virulence and defense are significantly affected by the deletion of HosA.

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The Rim15p homolog RimO mediates starvation response and is required for secondary metabolite production in Aspergillus nidulans

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