DNA damage-induced autophagy is regulated by inositol polyphosphate synthetases in Candida albicans

Abstract

DNA damage-induced autophagy is a new type of autophagy that differs from traditional macroautophagy; however, this type of autophagy has not been identified in the pathogenic fungus Candida albicans. Inositol polyphosphates are involved in the regulation of DNA damage repair and macroautophagy; however, whether inositol polyphosphates are involved in the regulation of DNA damage-induced autophagy remains unclear. In this study, we identified DNA damage-induced autophagy in C. albicans and systematically investigated the mechanisms of inositol polyphosphate pathway regulation. We found that the core machinery of macro autophagy is also essential for DNA damage-induced autophagy, and that inositol polyphosphate synthetases Kcs1, Ipk1, and Vip1 play a critical role in autophagy. In this study, we focused on Kcs1 and Vip1, which are responsible for the synthesis of inositol pyrophosphate. The kcs1Δ/Δ and vip1Δ/Δ strains exhibited reduced number of phagophore assembly sites (PAS) and autophagic bodies. The recruitment of autophagy-related gene 1 (Atg1) to PAS was significantly affected in the kcs1Δ/Δ and vip1Δ/Δ strains. Target of rapamycin complex 1 kinase activity was elevated in kcs1Δ/Δ and vip1Δ/Δ strains, which significantly inhibited the initiation of autophagy. Atg18 Localization was altered in these mutants. The absence of Kcs1 or Vip1 caused the downregulation of RAD53, a key gene in the DNA damage response. These data provide further understanding of the mechanism of autophagy regulation in C. albicans.

Keywords: Autophagosome biogenesis; Candida albicans; DNA damage-induced autophagy; Inositol polyphosphate synthetases; Phagophore assembly sites.