HOG pathway-dependent protection against impaired complex sphingolipid biosynthesis involves Fmp48-mediated suppression of mitochondria-dependent ROS accumulation.

Complex sphingolipids are required for normal growth of the budding yeast Saccharomyces cerevisiae. Repression of AUR1, which encodes inositol phosphorylceramide synthase, disrupts sphingolipid homeostasis by reducing complex sphingolipid levels and promoting ceramide accumulation, ultimately causing growth inhibition and cell death. We previously showed that the high-osmolarity glycerol (HOG) pathway is activated under AUR1-repressive conditions and alleviates the resulting growth defect. In this study, among genes induced in a HOG pathway-dependent manner, we identified FMP48, UIP4, and MGA1, whose overexpression suppressed cell death caused by AUR1 repression. Simultaneous deletion of these genes had modest effects under AUR1 repression alone but more clearly impaired cytoprotection when HOG pathway signaling was enhanced. Neither deletion nor overexpression of these genes restored complex sphingolipid levels or prevented ceramide accumulation. AUR1 repression promoted mitochondria-dependent ROS accumulation, and the associated cell death was markedly reduced when mitochondrial electron transport was impaired. Loss of HOG1 further enhanced ROS accumulation. FMP48 overexpression suppressed ROS accumulation and cell death in tet-AUR1 cells but did not further reduce cell death when mitochondrial electron transport was impaired. Together, these findings identify FMP48, UIP4, and MGA1 as contributors to HOG-dependent cytoprotection.