1. SUMO-targeted Ubiquitin Ligases as crucial mediators of protein homeostasis in Candida glabrata.
- Author
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Gupta, Dipika, Shukla, Renu, and Mishra, Krishnaveni
- Subjects
UBIQUITIN ligases ,PROTEOLYSIS ,POST-translational modification ,MYCOSES ,OPPORTUNISTIC infections - Abstract
Candida glabrata is an opportunistic human pathogen, capable of causing severe systemic infections that are often resistant to standard antifungal treatments. To understand the importance of protein SUMOylation in the physiology and pathogenesis of C. glabrata, we earlier identified the components of SUMOylation pathway and demonstrated that the deSUMOylase CgUlp2 is essential for pathogenesis. In this work we show that the CgUlp2 is essential to maintain protein homeostasis via the SUMO-targeted ubiquitin ligase pathway. The dual loss of deSUMOylase and specific ubiquitin ligase, CgSlx8, results in heightened protein degradation, rendering the cells vulnerable to various stressors. This degradation affects crucial processes such as purine biosynthesis and compromises mitochondrial function in the mutants. Importantly, the absence of these ubiquitin ligases impedes the proliferation of C. glabrata in macrophages. These findings underscore the significance of SUMOylation and SUMO-mediated protein homeostasis as pivotal regulators of C. glabrata physiology and capacity to survive in host cells. Understanding these mechanisms could pave the way for the development of effective antifungal treatments. Author summary: Opportunistic fungal infections are a major cause of mortality across the world. There are a limited number of antifungal drugs and many fungi are resistant to one or more of these. Therefore, there is an unmet need for new antifungals. As fungi are evolutionarily close to humans, identifying targets that are unique or sufficiently different from human counterparts is crucial/ our laboratory has been investigating if the post-translational modification pathway, SUMOylation, can be an effective target. To this end, we are studying the importance of this pathway in the pathogenic yeast, Candida glabrata, which is the second most common causative agent for candidiasis. We had earlier identified the components of this pathway and showed that this reversible protein modification was important for pathogenesis. Here, we investigated the mechanistic basis of the role of SUMOylation-deSUMOylation in C. glabrata infection and find that the balanced activity of this pathway is critical to maintain protein homeostasis in the cell. Perturbation of this pathway leads to unwarranted protein degradation rendering the cell incapable of combating stress including survival in host cells. Therefore, the SUMO-mediated protein homeostasis pathway in C. glabrata could be targeted for new antifungal development. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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