THE UBC8-GID E3 UBIQUITIN LIGASE MODULE IS REQUIRED FOR STRESS RESPONSE IN CANDIDA ALBICANS.

Authors

Zirong Zeng, Jakub Chrustowicz, Christos Spanos, Justyna Cholewa-Waclaw, Van Kelly, Yixin Zhao, Daniel H Scharf, Carol A Munro, Brenda A Schulman, Arno F Alpi, Vasso Makrantoni

Published in

The Journal of biological chemistry. Pages 113701. Oct 28, 2026. Epub Oct 28, 2026.

Abstract

Candida albicans is a leading cause of fungal infections in humans. To survive and proliferate within diverse and dynamic host niches, Candida must rapidly adapt, efficiently acquire essential nutrients, and mount protective stress responses. While cellular stress signalling networks are well described, regulation via the ubiquitin system, including E2-E3 ubiquitylation modules, remains largely unexplored in Candida. Here we investigate the multiprotein Glucose Induced Degradation Deficient (GID) E3 ubiquitin ligase complex and its cognate E2 conjugating enzyme, CaUbc8. Utilizing mass spectrometry-based proteomics, we identified conserved GID subunits, including the previously unannotated CaGid5 homologue. AlphaFold3 modelling predicted a conserved CaUbc8-GID E3 complex architecture, with modular features similar to the homologous Saccharomyces cerevisiae GID E3 complex, with CaGid5 functioning as the adaptor for the interchangeable substrate receptors CaGid4 and CaGid11. We observed that Candida cells responded to different stresses, including carbon source switching, heat shock, and osmotic stress, via a dynamic and differential expression of CaGid4 and CaGid11, suggesting the conditional assembly of distinct GID^CaGid4 and GID^CaGid11 E3 complexes. Notably, copper stress selectively enhanced the expression of CaGid4. Absence of CaGid4 receptor, GID E3 catalytic activity, or Ubc8 reduced copper stress-induced Candida growth and viability, and attenuated antifungal drug efficacy. System-wide proteomics analysis revealed CaGid4-dependent proteome and interactome dynamics implying modulation of oxidative stress response pathways. Together, our studies identified the multi-stress-responsive CaUbc8-GID E3 complex required for antifungal drug efficacy in Candida albicans, and we propose it as a new tractable target for the development of candidiasis therapeutics.

PMID:
42951139
Bibliographic data and abstract were imported from PubMed on 29 Oct 2026.

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