Stress granules plug and stabilize damaged endolysosomal membranes

Abstract Endomembrane damage represents a form of stress that is detrimental for eukaryotic cells 1,2 . To cope with this threat, cells possess mechanisms that repair the damage and restore cellular homeostasis 3–7 . Endomembrane damage also results in organelle instability and the mechanisms by which cells stabilize damaged endomembranes to enable membrane repair remains unknown. Here, by combining in vitro and in cellulo studies with computational modelling we uncover a biological function for stress granules whereby these biomolecular condensates form rapidly at endomembrane damage sites and act as a plug that stabilizes the ruptured membrane. Functionally, we demonstrate that stress granule formation and membrane stabilization enable efficient repair of damaged endolysosomes, through both ESCRT (endosomal sorting complex required for transport)-dependent and independent mechanisms. We also show that blocking stress granule formation in human macrophages creates a permissive environment for Mycobacterium tuberculosis , a human pathogen that exploits endomembrane damage to survive within the host.