Elevation of cell wall chitin via Ca²⁺–calcineurin‐mediated PKC signaling pathway maintains the viability of Candida albicans in the absence of β‐1,6‐glucan synthesis

Abstract

Summary β‐1,6‐glucan is an important cell wall component of Candida albicans. Deleted mutants of the two β‐1,6‐glucan synthase genes KRE6 and SKN1 are viable albeit with a range of defects including slow growth. It remains unclear whether β‐1,6‐glucan synthesis is not required under culture conditions or compensatory mechanisms exist in C. albicans. Here, we report that depleting β‐1,6‐glucan synthases leads to a significant increase in cell wall chitin levels through the posttranscriptional regulation of the chitin synthase Chs3 which maintains cell viability. And depleting β‐1,6‐glucan synthases in chs3Δ/Δ cells results in cell death. The elevation of cell wall chitin is mediated by the activation of the PKC signaling pathway and an unknown pathway(s) involving Ca2+–calcineurin. Also, kre6Δ/Δ skn1Δ/Δ cells are not more susceptible to caspofungin, the antifungal drug that inhibits β‐1,3‐glucan synthases, suggesting that β‐1,3‐glucan has no role in compensating β‐1,6‐glucan synthesis. Given the vital importance of elevating chitin synthesis in the absence of β‐1,6‐glucan synthesis in C. albicans, antifungal drugs targeting β‐1,6‐glucan and chitin synthesis could be used in combination therapies.

Phosphoric Metabolites Link Phosphate Import and Polysaccharide Biosynthesis for Candida albicans Cell Wall Maintenance

“…Unlike Han et al (59), we found that very low nikkomycin concentrations further inhibit the growth of KRE6-depleted cells, as compensatory chitin synthesis is inhibited (Fig. 8B).…”

“…We found a higher chitin content in cells depleted of KRE6, as previously reported (59). This effect was completely or partially abrogated in cells lacking Pho84 (Fig.…”

“…Growth defects of strains that we constructed in which expression of the genes encoding the major beta-1,6-glucan synthase, KRE6, and the single essential chitin synthase, CHS1, is repressible from pMAL2 ( Fig. 6 and 7) or tetO were in agreement with the results of Munro et al (55) but differed from the findings of Han et al (18,59). In some kre6/pMAL2-KRE6 strains, we also deleted the minor beta-1,6-glucan synthaseencoding gene, SKN1, and observed no further effect on the phenotype under the analyzed conditions.…”

“…8A) in cells depleted of KRE6. Han et al showed that this response depended on intact Mkc1 signaling (59). Absence of Pho84 in KRE6-depleted cells abrogated this compensatory response (Fig.…”

Sphingolipids: Regulators of azole drug resistance and fungal pathogenicity

“…Additionally, PHS‐1‐P as signaling molecules also can directly activate the conserved calcium responsive calcineurin‐Crz1 pathway in S. cerevisiae (Birchwood et al ., 2001). Considering the importance of the calcineurin‐Crz1 pathway in cell wall synthesis and maintenance (de Castro et al ., 2019; Han et al ., 2019b), it is possible that PHS‐1‐P regulates CWI by activating calcium signaling pathway. Taken together, sphingolipid can integrate multiple signaling pathways to regulate cell wall synthesis and maintenance (Dickson, 2010).…”