Light-dependent coordination of development and secondary metabolism in the filamentous fungus Aspergillus nidulans

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Asexual reproduction of the filamentous fungus Aspergillus nidulans is accelerated by light, whereas sexual spores within closed protecting overwintering fruiting bodies are preferentially formed in darkness. Differentiation programs are tightly connected to distinct secondary metabolic pathways, which are encoded by genes, which are in fungi often clustered on one chromosomal locus. Secondary metabolite biosynthetic gene clusters are silenced during vegetative growth and only expressed under specific conditions as e.g. during development. This research project aims to characterize the interplay between homo/hetero-dimeric transcriptional regulators, epigenetic methyltransferases and substrate receptors for protein degradation and fungal development, virulence and secondary metabolism. The focus is on their functions in development and secondary metabolite formation in A. nidulans and virulence in A. fumigatus. Velvet domain proteins interacting with each other and with different Vap-Vip methyltransferases, and F-box protein substrate receptors of E3 cullin RING ubiquitin ligases will be analyzed. The 150-200 amino acid velvet domain provides DNA binding and dimerization to hundreds of fungal genes to coordinate development and secondary metabolism. Heterodimer formation can be controlled by the synthesis and degradation of subunits or by controlled addition and removal of posttranslational modifications. Only the velvet protein VelB is interrupted by an insertion of an intrinsically disordered domain (IDD) and can be part of two different heterodimers: VosA-VelB delays asexual development and promotes spore viability, whereas VeA-VelB supports sexual development. We will explore whether the inserted VelB intrinsically disordered domain (IDD) provides selective heterodimer formation (for VosA) as additional level of control, which might be combined with other control mechanisms as stability, posttranslational modifications or location. The A. nidulans VapB-VipC system will be compared with A. fumigatus, which carries two isogenes for velvet interacting protein VipC (VipC1, VipC2) and includes strains with or without VapB and where the impact on pathogenicity will be explored. The link between cellular protein stability control and genetic networks for light-controlled fungal development, secondary metabolism and virulence will be examined through the characterization of fungal F-box protein receptor subunits, which recognize primed substrates to be ubiquitinated. The 74 genes for putative F-box protein substrate receptors of A. nidulans include seven developmental-specific receptors. The deletion collection of Fbox protein encoding genes, which we have constructed during the last years, will allow to study degradation of velvet domain proteins, but also the function of Fbx in secondary metabolism, stress response, development and (at least for Fbx15) virulence.