Phospholipid imbalance impairs autophagosome completion. (27th October 2022)

• Record Type: Journal Article
• Authors: Polyansky, Alexandra; Shatz, Oren; Fraiberg, Milana; Shimoni, Eyal; Dadosh, Tali; Mari, Muriel; Reggiori, Fulvio M; Qin, Chao; Han, Xianlin; Elazar, Zvulun
• Is Part Of: EMBO journal. Volume 41:Number 23(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-10-27
• Subjects: autophagosome biogenesis -- autophagy -- phagophore -- phospholipids; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2022110771
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Autophagy, a conserved eukaryotic intracellular catabolic pathway, maintains cell homeostasis by lysosomal degradation of cytosolic material engulfed in double membrane vesicles termed autophagosomes, which form upon sealing of single‐membrane cisternae called phagophores. While the role of phosphatidylinositol 3‐phosphate (PI3P) and phosphatidylethanolamine (PE) in autophagosome biogenesis is well‐studied, the roles of other phospholipids in autophagy remain rather obscure. Here we utilized budding yeast to study the contribution of phosphatidylcholine (PC) to autophagy. We reveal for the first time that genetic loss of PC biosynthesis via the CDP‐DAG pathway leads to changes in lipid composition of autophagic membranes, specifically replacement of PC by phosphatidylserine (PS). This impairs closure of the autophagic membrane and autophagic flux. Consequently, we show that choline‐dependent recovery of de novo PC biosynthesis via the CDP‐choline pathway restores autophagosome formation and autophagic flux in PC‐deficient cells. Our findings therefore implicate phospholipid metabolism in autophagosome biogenesis. Synopsis: The autophagic membrane has a characteristic lipid composition. Phospholipid imbalance within this membrane, especially the substitution of phosphatidylcholine (PC) by phosphatidylserine (PS), leads to phagophores which are unable to close. Loss of PC synthesis impairs autophagosome completion. Replacement of PC by PS in the phagophore maintains growth but impairs closure. De novo PC synthesis by the CDP‐Choline pathway restores autophagosome completion in CDP‐DAG mutant cells. Abstract : A relatively high ratio of phosphatidylcholine to phosphatidylserine drives closure of the autophagosome membrane.