Assembly of a heptameric STRIPAK complex is required for coordination of light-dependent multicellular fungal development with secondary metabolism in Aspergillus nidulans.

Nadia Elramli,Mevlüt Ulas,Betim Karahoda,Dean Frawley,C Elizabeth Oakley,Berl R Oakley,Özlem Sarikaya-Bayram,Özgür Bayram,Stephan Seiler,Michael Freitag

doi:10.1371/journal.pgen.1008053

Abstract

Eukaryotic striatin forms striatin-interacting phosphatase and kinase (STRIPAK) complexes that control many cellular processes including development, cellular transport, signal transduction, stem cell differentiation and cardiac functions. However, detailed knowledge of complex assembly and its roles in stress responses are currently poorly understood. Here, we discovered six striatin (StrA) interacting proteins (Sips), which form a heptameric complex in the filamentous fungus Aspergillus nidulans. The complex consists of the striatin scaffold StrA, the Mob3-type kinase coactivator SipA, the SIKE-like protein SipB, the STRIP1/2 homolog SipC, the SLMAP-related protein SipD and the catalytic and regulatory phosphatase 2A subunits SipE (PpgA), and SipF, respectively. Single and double deletions of the complex components result in loss of multicellular light-dependent fungal development, secondary metabolite production (e.g. mycotoxin Sterigmatocystin) and reduced stress responses. sipA (Mob3) deletion is epistatic to strA deletion by supressing all the defects caused by the lack of striatin. The STRIPAK complex, which is established during vegetative growth and maintained during the early hours of light and dark development, is mainly formed on the nuclear envelope in the presence of the scaffold StrA. The loss of the scaffold revealed three STRIPAK subcomplexes: (I) SipA only interacts with StrA, (II) SipB-SipD is found as a heterodimer, (III) SipC, SipE and SipF exist as a heterotrimeric complex. The STRIPAK complex is required for proper expression of the heterotrimeric VeA-VelB-LaeA complex which coordinates fungal development and secondary metabolism. Furthermore, the STRIPAK complex modulates two important MAPK pathways by promoting phosphorylation of MpkB and restricting nuclear shuttling of MpkC in the absence of stress conditions. SipB in A. nidulans is similar to human suppressor of IKK-ε(SIKE) protein which supresses antiviral responses in mammals, while velvet family proteins show strong similarity to mammalian proinflammatory NF-KB proteins. The presence of these proteins in A. nidulans further strengthens the hypothesis that mammals and fungi use similar proteins for their immune response and secondary metabolite production, respectively.

Highlights

Signaling pathways that regulate morphological and physiological processes in response to stimuli are often highly conserved throughout eukaryotes, signifying their importance
The multisubunit striatin-interacting phosphatase and kinase (STRIPAK) complex has been studied from yeast to human and plays a range of roles from cell-cycle arrest, fruit body formation to neuronal functions
In filamentous fungus Aspergillus nidulans, we found a heptameric STRIPAK core complex made from three subcomplexes, which sits on the nuclear envelope and coordinates signal influx for lightdependent fungal development, secondary metabolism and stress responses

Summary

Introduction

Signaling pathways that regulate morphological and physiological processes in response to stimuli are often highly conserved throughout eukaryotes, signifying their importance. It forms a scaffolding platform to build the striatin-interacting phosphatase and kinase (STRIPAK) complex which is a large multimeric protein complex highly conserved in eukaryotes [3]. The STRIPAK complex influences mammalian cell size, morphology and migration [1]. It plays a role in the polarisation of the golgi apparatus and is implicated in the process of mitosis through tethering vesicles of the golgi to the nuclear membrane and centrosomes [4]. The mammalian STRIPAK complex consists of a multitude of core members which include (i) Striatins (ii) Striatin-interacting proteins (STRIP1/STRIP2), (iii) monopolar spindle onebinder (Mob3/phocein) protein, [5], (iv) cerebral cavernous malformation 3 protein, CCM3 (v) and the phosphatase 2A subunits PP2AA and PP2Ac that have structural and catalytic functions, respectively. The GCKs were discovered to be involved in the control of the cell cycle, polarity and migration [7, 8] and their functionality is reliant on CCM3 which is involved in stabilising the kinases [9]

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Conclusion