Systems-level phosphoproteomics reveals conserved and subunit-specific STRIPAK signaling networks in Cryptococcus neoformans

Authors

Peterson, P. P., Croog, S., Choi, Y., Choi, J.-T., Bahn, Y.-S., Heitman, J.

Abstract

The striatin-interacting phosphatase and kinase (STRIPAK) complex is a conserved PP2A-associated signaling hub that integrates kinase-phosphatase networks, yet its roles in human fungal pathogens remain poorly defined. Here, we dissected STRIPAK functions in the opportunistic pathogen Cryptococcus neoformans by combining genetic, genomic, virulence, and systems-level phosphoproteomic analyses across mutants lacking individual STRIPAK subunits. Loss of the core STRIPAK components via PPH22, FAR8, FAR9, or FAR11 mutations caused severe defects in growth, stress adaptation, cell-cycle progression, and morphogenesis, accompanied by widespread aneuploidy and genome instability. In murine infection models, far11{Delta} strains were avirulent, whereas far9{Delta} mutants caused delayed but ultimately fatal disease and underwent host-associated genome remodeling, with all recovered isolates acquiring chromosome 11 tetraploidy despite no consistent in vitro fitness advantage. In striking contrast, deletion of MOB3 produced a hypervirulent phenotype. mob3{Delta} cells exhibited enhanced transmigration across an in vitro blood-brain barrier model, increased survival in macrophages, and generated abundant small-cell morphotypes in vitro and in vivo, features associated with increased dissemination. Global phosphoproteomic profiling revealed extensive and overlapping phosphorylation changes among core STRIPAK mutants, affecting pathways involved in signaling, cytoskeletal and cell-cycle control, chromatin and transcriptional regulation, RNA metabolism, and stress responses. By contrast, mob3{Delta} mutants displayed a smaller, largely distinct phosphoproteomic signature. Network and functional enrichment analyses highlighted STRIPAK-dependent regulation of MAPK/GTPase signaling, autophagy, nuclear transport, RNA processing, DNA replication, and ribosome biogenesis. Together, these findings establish STRIPAK as a central coordinator of genome stability, morphological plasticity, and virulence in C. neoformans, and demonstrate that individual STRIPAK subunits drive shared yet divergent signaling outputs that shape host-pathogen interactions.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 06 Jan 2026.

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