The genotoxic stress-inducible gene GEI1(Orf19.3109) is a repressor of virulence in Candida albicans

Abstract

ABSTRACT Transcriptional reprogramming under genotoxic stress is essential for the survival and pathogenesis of Candida albicans. While many DNA damage response (DDR) genes are well-characterized, the functions of pathogen-specific, stress-inducible genes remain poorly understood. Here, we characterized GEI1 (Orf19.3109), a gene significantly induced by genotoxic agents and oxidative stress, which lacks a clear ortholog in Saccharomyces cerevisiae. Interestingly, although GEI1 expression is triggered by DNA damage stress, its deletion does not impair genotoxin tolerance. Instead, the gei1Δ mutant shows increased resistance to oxidative stress, characterized by reduced intracellular reactive oxygen species (ROS) accumulation. Furthermore, loss of GEI1 leads to hyper-secretion of extracellular aspartyl proteases (Saps) and results in a hypervirulence phenotype in the Galleria mellonella infection model. Transcriptomic profiling and CRISPR-interference (CRISPRi) assays revealed that loss of GEI1 function triggers the hyperactivation of antioxidant defenses and protease secretion. We demonstrate that the hypervirulence of the gei1Δ mutant is primarily driven by the transcriptional derepression of SAP1, SAP3, SAP5 and the putative alcohol dehydrogenase ADH4. Repression of these downstream effectors in the gei1Δ background reduced protease secretion and restored virulence to wild-type levels. Overall, our findings uncouple transcriptional induction from conventional DNA repair functions and reveal a novel regulatory checkpoint where GEI1 links genotoxic stress signaling to the suppression of key pathogenic traits, highlighting a complex strategy by which C. albicans balances stress adaptation and virulence control.