Ifu5, a WW domain‐containing protein interacts with Efg1 to achieve coordination of normoxic and hypoxic functions to influence pathogenicity traits inCandida albicans

Abstract

Hypoxic adaptation pathways, essential for Candida albicans pathogenesis, are tied to its transition from a commensal to a pathogen. Herein, we identify a WW domaincontaining protein, Ifu5, as a determinant of hypoxic adaptation that also impacts normoxic responses in this fungus. Ifu5 activity supports glycosylation homeostasis via the Cek1 mitogen-activated protein kinase-dependent up-regulation of PMT1, under normoxia. Transcriptome analysis of ifu5Δ/Δ under normoxia shows a significant up-regulation of the hypoxic regulator EFG1 and EFG1-dependent genes. We demonstrate physical interaction between Ifu5 by virtue of its WW domain and Efg1 that represses EFG1 expression under normoxia. This interaction is lost under hypoxic growth conditions, relieving EFG1 repression. Hypoxic adaptation processes such as filamentation and biofilm formation are affected in ifu5Δ/Δ cells revealing the role of Ifu5 in hypoxic signalling and modulating pathogenicity traits of C. albicans under varied oxygen conditions. Additionally, the WW domain of Ifu5 facilitates its role in hypoxic adaptation, revealing the importance of this domain in providing a platform to integrate various cellular processes. These data forge a relationship between Efg1 and Ifu5 that fosters the role of Ifu5 in hypoxic adaptation thus illuminating novel strategies to undermine the growth of C. albicans.

EFG1, Everyone’s Favorite Gene in Candida albicans: A Comprehensive Literature Review

“…Under normoxic conditions expression of Efg1 is suppressed through interactions with Ifu5 ( Rastogi et al., 2020 ) Following the transition to a hypoxic environment suppression of Efg1 by Ifu5 decreases, and as a result Efg1 expression increases. Under these hypoxic conditions Efg1 downregulates CEK1 and CPH1 , components of the CEK1 MAP (Mitogen Activated Protein) kinase cascade required for filamentation ( Desai et al., 2015 ).…”

Transcriptional Control of Hypoxic Hyphal Growth in the Fungal Pathogen Candida albicans

“…In opposite to Efg1-Bcr1 regulatory axis, the transcription factor Ace2 promotes filamentation under hypoxia ( Mulhern et al., 2006 ) but also in response to the hyphae-promoting growth medium, Spider ( Noble et al., 2010 ). Many other regulatory proteins were also essential for the C. albicans morphogenesis under hypoxia, however, they were also required to signal in response to other filamentation cues ( Jr et al., 1999 ; Sellam et al., 2010 ; Spiering et al., 2010 ; Stichternoth et al., 2011 ; Bi et al., 2018 ; Burgain et al., 2019 ; Rastogi et al., 2020 ).…”

Recent Advances in Understanding the Human Fungal Pathogen Hypoxia Response in Disease Progression

“…Transcription of EFG1 in oxygen-replete conditions is repressed through the WW domain-mediated binding of Efg1 by Ifu5. The transition to a low-oxygen environment relieves this regulation, allowing for the transcription of EFG1 and the downstream effects of Efg1 in oxygen-limited environments (104). An in silico study recently reported the possibility of utilizing naturally occurring polyphenols to regulate Efg1 activity as a possible future treatment option (90).…”