ATG9A protects the plasma membrane from programmed and incidental permeabilization

• Published in: Nature cell biology Vol. 23; no. 8; pp. 846 - 858
• Main Authors: Claude-Taupin, Aurore, Jia, Jingyue, Bhujabal, Zambarlal, Garfa-Traoré, Meriem, Kumar, Suresh, da Silva, Gustavo Peixoto Duarte, Javed, Ruheena, Gu, Yuexi, Allers, Lee, Peters, Ryan, Wang, Fulong, da Costa, Luciana Jesus, Pallikkuth, Sandeep, Lidke, Keith A., Mauthe, Mario, Verlhac, Pauline, Uchiyama, Yasuo, Salemi, Michelle, Phinney, Brett, Tooze, Sharon A., Mari, Muriel C., Johansen, Terje, Reggiori, Fulvio, Deretic, Vojo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2021; Nature Publishing Group; Nature Research
• Subjects: 631/80/313; 631/80/313/2155; 631/80/39/2346; Autophagosomes - metabolism; Autophagy; Autophagy (Cytology); Autophagy-Related Proteins - genetics; Autophagy-Related Proteins - metabolism; Biology; Biomedical and Life Sciences; Cancer Research; Cell Biology; Cell Membrane - metabolism; Cell membranes; Cell research; Cellular control mechanisms; Coronaviruses; Damage; Developmental Biology; Genetic aspects; Health sciences; HEK293 Cells; HeLa Cells; Humans; Immunoblotting; Immunoprecipitation; IQGAP1 protein; Kinases; Life Sciences; Ligands; Lipids; Medical research; Membrane proteins; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membranes; Metabolism; Microorganisms; Microscopy; Microscopy, Confocal; Phagocytosis; Plasma; Properties; Protein Transport - physiology; Proteins; Stem Cells; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism; United States
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-021-00706-w

The integral membrane protein ATG9A plays a key role in autophagy. It displays a broad intracellular distribution and is present in numerous compartments, including the plasma membrane (PM). The reasons for the distribution of ATG9A to the PM and its role at the PM are not understood. Here, we show that ATG9A organizes, in concert with IQGAP1, components of the ESCRT system and uncover cooperation between ATG9A, IQGAP1 and ESCRTs in protection from PM damage. ESCRTs and ATG9A phenocopied each other in protection against PM injury. ATG9A knockouts sensitized the PM to permeabilization by a broad spectrum of microbial and endogenous agents, including gasdermin, MLKL and the MLKL-like action of coronavirus ORF3a. Thus, ATG9A engages IQGAP1 and the ESCRT system to maintain PM integrity. Claude-Taupin et al. show that ATG9A mediates protection against plasma membrane damage in diverse biological contexts through a mechanism involving IQGAP1 and ESCRTs.