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Here, we dissected STRIPAK functions in the opportunistic pathogen\n                      <jats:italic toggle=\"yes\">Cryptococcus neoformans<\/jats:italic>\n                      by combining genetic, genomic, virulence, and phosphoproteomic analyses across mutants lacking individual STRIPAK subunits. Loss of the core STRIPAK components via\n                      <jats:italic toggle=\"yes\">PPH22<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">FAR8<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">FAR9<\/jats:italic>\n                      , or\n                      <jats:italic toggle=\"yes\">FAR11<\/jats:italic>\n                      mutations caused severe defects in growth, stress adaptation, cell cycle progression, and morphogenesis, accompanied by widespread aneuploidy and genome instability. In murine infection models,\n                      <jats:italic toggle=\"yes\">far11<\/jats:italic>\n                      \u0394 strains were avirulent, whereas\n                      <jats:italic toggle=\"yes\">far9<\/jats:italic>\n                      \u0394 mutants caused delayed but ultimately fatal disease and underwent host-associated genome remodeling, with recovered isolates exhibiting chromosome 11 amplification despite no consistent\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      fitness advantage. In contrast, deletion of\n                      <jats:italic toggle=\"yes\">MOB3<\/jats:italic>\n                      produced a hypervirulent phenotype.\n                      <jats:italic toggle=\"yes\">mob3<\/jats:italic>\n                      \u0394 cells exhibited enhanced transmigration across an i\n                      <jats:italic toggle=\"yes\">n vitro<\/jats:italic>\n                      blood-brain barrier model, increased survival in macrophages, and generated small-cell morphotypes, features associated with increased dissemination. Phosphoproteomic profiling revealed extensive and overlapping phosphorylation changes among core STRIPAK mutants, affecting pathways involved in signaling, cytoskeletal, cell cycle control, chromatin regulation, RNA metabolism, and stress responses. Conversely,\n                      <jats:italic toggle=\"yes\">mob3<\/jats:italic>\n                      \u0394 mutants displayed a smaller, largely distinct phosphoproteomic signature. Network and functional enrichment analyses highlighted STRIPAK-dependent regulation of TORC2-associated signaling, MAPK\/GTPase signaling, autophagy, nuclear transport, RNA processing, DNA replication, and ribosome biogenesis. Together, these findings establish STRIPAK as a coordinator of genome stability, morphological plasticity, stress adaptation, and virulence in\n                      <jats:italic toggle=\"yes\">C. neoformans<\/jats:italic>\n                      , and demonstrate that individual STRIPAK subunits drive shared yet divergent signaling outputs that shape host-pathogen interactions.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Fungal pathogens must rapidly adapt their growth, morphology, and stress responses to survive within the host, requiring precise coordination of cellular signaling pathways. The conserved striatin-interacting phosphatase and kinase (STRIPAK) complex controls key developmental programs in eukaryotes, but its roles in fungal pathogenesis are not fully defined. We previously showed that STRIPAK is important for genome stability, development, and virulence in the opportunistic human fungal pathogen\n                        <jats:italic toggle=\"yes\">Cryptococcus neoformans<\/jats:italic>\n                        . Here, we define how individual STRIPAK subunits differentially regulate fungal morphogenesis, genome plasticity, host adaptation, and virulence, revealing both shared and subunit-specific functions within this conserved signaling complex. Core STRIPAK mutants exhibit severe growth and stress-response defects and attenuation of virulence, whereas loss of the Mob3 subunit promotes hypervirulence by enhancing dissemination and persistence within the host. Phosphoproteomic profiling reveals that individual STRIPAK components exert shared yet distinct control over phosphorylation networks that shape host-pathogen interactions, establishing STRIPAK as a central signaling hub and a potential target for antifungal intervention.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01737-26","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:01:20Z","timestamp":1786626080000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Distinct STRIPAK subunits drive conserved and subunit-specific signaling programs in\n                    <i>Cryptococcus neoformans<\/i>"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0630-1045","authenticated-orcid":true,"given":"Patricia 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