Role of methyltransferases in fungal development and secondary metabolite production

Abstract

Fungal development and secondary metabolism are controlled by environmental signals through regulatory proteins. VeA protein is the founding member of the velvet superfamily of fungal regulators. It is involved in light response and coordinates sexual reproduction and secondary metabolism in Aspergillus nidulans. In the dark, VeA bridges VelB and LaeA proteins to form the VelB-VeA-LaeA (velvet) complex. The VeA-like protein VelB is a developmental regulator, whereas LaeA has been known as global regulator of secondary metabolism. In the first part of this study, it was shown that VelB forms a second light-regulated complex together with VosA, another member of the velvet family, which represses asexual development. LaeA directs the formation of the VelB-VosA and VelB-VeA-LaeA complexes and coordinates secondary metabolism during development. The laeA null mutant results in constitutive sexual differentiation, indicating that LaeA plays a pivotal role in inhibiting sexual development in response to light. Moreover, the absence of LaeA results in formation of significantly smaller fruiting bodies, which is due to the lack of a specific globose cell type (Hulle cells) that nurses the young fruiting body during development. This suggests that LaeA plays a dynamic role in fungal morphological and chemical development, and controls expression, interactions and modification of the velvet regulators. VeA represents a platform for protein-protein interactions for regulation of development and secondary metabolism. VeA platform function was further studied in the second part of this study, which focused on novel VeA interacting proteins (Vips) and their interaction partners. A yeast two-hybrid screen using VeA as bait led to the identification of a trimeric methyltransferase complex that connects signal transduction to epigenetic control. The novel complex contains the plasma membrane associated trimeric VapA-VipC-VapB proteins. The VipC-VapB heterodimeric methyltransferases of the complex are tethered to the plasma membrane by the FYVE-like zinc finger protein VapA allowing the nuclear VelB-VeA-LaeA complex to activate transcription for sexual development. Once the release from VapA is triggered, VipC-VapB is transported into the nucleus. VipC-VapB physically interacts with VeA, impairs its nuclear import and protein stability, which in consequence reduces the level of nuclear VelB-VeA-LaeA complex. Nuclear VapB methyltransferase diminishes the establishment of facultative heterochromatin by decreasing histone 3 lysine 9 trimethylation (H3K9 me3). This favors the activation of early regulatory genes flbA and flbC, which promotes the asexual program in presence of light. The VapA-VipC-VapB methyltransferase pathway combines control of nuclear import and stability of transcription factors with histone modification to foster appropriate differentiation responses.