ATG9A-mediated plasma membrane repair is linked to Vps13A and regulated by glycosylation

Biological membranes provide a resilient framework for cellular structure and stability. Disrupting its integrity may result in irreparable damage, altering cellular homeostasis and ultimately leading to cell death. ATG9A, a transmembrane protein, has recently been implicated in plasma membrane repair. However, its role in the process and the mechanism by which it is targeted to the plasma membrane upon damage are unclear. We show here that glycosylation of ATG9A is essential for its membrane repair activity. This has been corroborated by using different mutant cells that are defective in their ability to process proteoglycan in the Golgi complex. Specifically, sialylation of the sugar moiety appears vital for plasma membrane repair activity. Additionally, we provide evidence indicating that ATG9A is targeted to the plasma membrane through interaction with the endosomal sorting complex required for transport complex. Finally, we found that ATG9A lipid scramblase activity and the lipid transfer protein VPS13A are needed for efficient membrane repair.