The ubiquitous ARV1 gene shows significant functional conservation across eukaryotes. Saccharomyces cerevisiae Arv1 is implicated in several cellular processes, including lipid/sterol homeostasis, morphogenesis, and drug resistance. Human and fungal ARV1 functionally complement S. cerevisiae ARV1, and arv1Δ is rescued by the overexpression of some subunits of the GPI-N-acetylglucosaminyltransferase (GPI-GnT), which catalyzes the first GPI biosynthetic step. Human and Trypanosoma brucei Arv1 homologs co-immunoprecipitate with different GPI-GnT subunits. Based on these previous reports, we hypothesized a cross talk between Candida albicans ARV1 and the first step of GPI biosynthesis. Using super-resolution radial fluctuation (SRRF) analysis of co-localization data, co-immunoprecipitation assays, and acceptor-photobleaching FRET studies, we show that CaArv1 physically interacts with the GPI-GnT. It also regulates the expression of the GPI-GnT subunits via the epigenetic modulator, Rtt109. Overexpressing GPI19 (which encodes a GPI-GnT subunit whose expression is repressed in Caarv1Δ/Δ) rescues its cell wall phenotype, sensitivity to azoles, and GPI-GnT activity without reversing the filamentation defect. A similar rescue is observed on downregulating GPI2 (encoding another GPI-GnT subunit, whose expression is upregulated in Caarv1Δ/Δ). Thus, transcriptional control rather than physical interaction appears to be the primary mechanism by which CaArv1 controls GPI-GnT. Overexpressing RAS1 restores all phenotypes, including filamentation, without restoring GPI-GnT activity. The filamentation defect of Caarv1Δ/Δ is independent of the GPI-GnT. CaArv1 transcriptionally regulates hyphae-specific transcription factors downstream of cAMP-PKA signaling (Efg1, Flo8) and repressors (Tup1, Nrg1) to modulate filamentation. The cross talk between CaArv1 and GPI-GnT has important implications for the virulence of C. albicans.

• PMID: 40801327
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Journal Article

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Bharati M, Saini H, Thakran N, Kumar Y, Shefali S, Yadav U, Saun S, Anzar A, Komath SS

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