Cryptococcus neoformans rewires the conserved Wee1-CDK checkpoint through two divergent kinases required for replication-stress tolerance and virulence

Abstract

Cell-cycle checkpoints couple cell division to environmental and intracellular stress. Here, we show that the human fungal pathogen Cryptococcus neoformans possesses two divergent Wee1-family kinases, CnSwe1 and CnSwe102, that retain conserved CDK-inhibitory activity but function differently from their counterparts in the canonical Saccharomyces cerevisiae morphogenesis checkpoint. The swe1{Delta} and swe102{Delta} mutants displayed distinct stress-response defects, and genetic analyses suggested a dosage-sensitive genetic interaction between SWE1 and SWE102. Although both proteins promoted Cdc28 tyrosine phosphorylation and elongated-cell morphology when expressed in S. cerevisiae, neither localized to the mother-bud neck in C. neoformans. Altered SWE1 dosage in the absence of SWE102 increased sensitivity to replicative and DNA-damaging stresses and perturbed cell-cycle progression under genotoxic conditions. Importantly, loss of SWE1 nearly abolished virulence in a murine infection model, and SWE102 also contributed to pathogenicity. Together, these findings indicate that the conserved Wee1-CDK module acts in C. neoformans as a dosage-sensitive checkpoint that promotes stress adaptation and fungal virulence.