Autophagy is regulated by endoplasmic reticulum calcium homeostasis and sphingolipid metabolism.

Calcium is involved in a variety of cellular processes. As the crucial components of cell membranes, sphingolipids also play important roles as signaling molecules. Intracellular calcium homeostasis, autophagy initiation and sphingolipid synthesis are associated with the endoplasmic reticulum (ER). Recently, through genetic screening and lipidomics analysis in Saccharomyces cerevisiae, we found that the ER calcium channel Csg2 converts sphingolipid metabolism into macroautophagy/autophagy regulation by controlling ER calcium homeostasis. The results showed that Csg2 acts as a calcium channel to mediate ER calcium efflux into the cytoplasm, and deletion of CSG2 causes a distinct increase of ER calcium concentration, thereby disrupting the stability of the sphingolipid synthase Aur1, leading to the accumulation of the bioactive sphingolipid phytosphingosine (PHS), which specifically and completely blocks autophagy. In summary, our work links calcium homeostasis, sphingolipid metabolism, and autophagy initiation via the ER calcium channel Csg2.