Extended Data Fig. 10: Summary illustration of the phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair.
From: A phosphoinositide signalling pathway mediates rapid lysosomal repair
(1) LMP-induced Ca2+ release triggers the rapid lysosomal recruitment of PI4K2A that generates high levels of PtdIns4P on damaged lysosomes. (2) Lysosomal PtdIns4P in turn recruits and stimulates ORP9/10/11 to establish extensive ER-lysosome membrane contacts and mediate subsequent ER-to-lysosome phosphatidylserine (PS) transport. (3) Lysosomal accumulation of PS activates the lipid transporter ATG2 which delivers large amounts of lipids to lysosomes for direct membrane repair. (4) Downstream of PtdIns4P signaling and in parallel of ORP9/10/11, OSBP acts as a redundant membrane tether which transports cholesterol (Chol) rather than PS to damaged lysosomes. Due to the intrinsic capability of cholesterol to improve membrane rigidity and stability, lysosomal cholesterol accumulation might directly assist in membrane repair.
