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bioRxiv · 10.1101/2024.02.28.582498

The ER-resident Ras Inhibitor 1 (Eri1) of Candida albicans inhibits hyphal morphogenesis via the Ras-independent cAMP-PKA pathway

Komath, S. S.·Sethi, S. C.·Bharati, M.·Yadav, U.·Kumar, Y.
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Abstract

Ras signaling and glycosylphosphatidylinositol (GPI) biosynthesis are mutually inhibitory in S. cerevisiae. The inhibition is mediated via an interaction of yeast Ras2 with the Eri1 subunit of its GPI-N-acetylglucosaminyl transferase (GPI-GnT), the enzyme catalyzing the very first GPI biosynthetic step. In contrast, Ras signaling and GPI biosynthesis in C. albicans are mutually activated and together control the virulence traits of the human fungal pathogen. What might be the role of Eri1 in this pathogen? The present manuscript addresses this question while simultaneously characterizing the cellular role of CaEri1. It is either non-essential or required at very low levels for cell viability in C. albicans. Severe depletion of CaEri1 results in reduced GPI biosynthesis and cell wall defects. It also produces hyperfilamentation phenotypes in Spider medium as well as in bicarbonate medium containing 5% CO2, suggesting that both the Ras-dependent and Ras-independent cAMP-PKA pathways for hyphal morphogenesis are activated in these cells. Pull-down and acceptor-photobleaching FRET experiments suggest that CaEri1 does not directly interact with CaRas1, but does so through CaGpi2, another GPI-GnT subunit. CaGpi2 is also downstream of CaEri1 in cross-talk with CaRas1 and control of hyphal growth in Spider medium. However, CaEri1 is downstream of all GPI-GnT subunits in inhibiting Ras-independent filamentation. CaERI1 also participates in the inter-subunit transcriptional cross-talk within the GPI-GnT, a feature unique to C. albicans. Virulence studies using G. mellonella larvae show that a heterozygous strain of CaERI1 is better cleared by the host and is attenuated in virulence.

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Komath, S. S., Sethi, S. C., Bharati, M., Yadav, U., Kumar, Y.. 2024-02-28. The ER-resident Ras Inhibitor 1 (Eri1) of Candida albicans inhibits hyphal morphogenesis via the Ras-independent cAMP-PKA pathway. https://doi.org/10.1101/2024.02.28.582498

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