GABARAP sequesters the FLCN-FNIP tumor suppressor complex to couple autophagy with lysosomal biogenesis
Jonathan M. Goodwin, Ward G. Walkup, Kirsty M. Hooper, Taoyingnan Li, Chieko Kishi‐Itakura, Aylwin Ng, Timothy Z. Lehmberg, Archana Jha, Sravya Kommineni, Katherine Fletcher, Jorge García‐Fortanet, Yaya Fan, Qing Tang, Menghao Wei, Asmita Agrawal, Sagar R. Budhe, Sreekanth R. Rouduri, Dan Baird, Jeff Saunders, Janna Kiselar, Mark R. Chance, Andrea Ballabio, B.A. Appleton, John H. Brumell, Oliver Florey, Leon O. Murphy
Abstract
-induced xenophagy, the membrane conjugation of GABARAP, but not LC3, is required for activation of TFEB/TFE3 to control lysosomal capacity. GABARAP directly binds to a previously unidentified LC3-interacting motif (LIR) in the FLCN/FNIP tumor suppressor complex and mediates sequestration to GABARAP-conjugated membrane compartments. This disrupts FLCN/FNIP GAP function toward RagC/D, resulting in impaired substrate-specific mTOR-dependent phosphorylation of TFEB. Thus, the GABARAP-FLCN/FNIP-TFEB axis serves as a molecular sensor that coordinates lysosomal homeostasis with perturbations and cargo flux within the autophagy-lysosomal network.