Mammalian Atg8 proteins regulate lysosome and autolysosome biogenesis through SNAREs. (18th October 2019)

• Record Type: Journal Article
• Authors: Gu, Yuexi; Princely Abudu, Yakubu; Kumar, Suresh; Bissa, Bhawana; Choi, Seong Won; Jia, Jingyue; Lazarou, Michael; Eskelinen, Eeva‐Liisa; Johansen, Terje; Deretic, Vojo
• Is Part Of: EMBO journal. Volume 38:Number 22(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-10-18
• Subjects: autophagy -- GABARAP -- lysosome -- SNARE -- TOR; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2019101994
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Mammalian homologs of yeast Atg8 protein (mAtg8s) are important in autophagy, but their exact mode of action remains ill‐defined. Syntaxin 17 (Stx17), a SNARE with major roles in autophagy, was recently shown to bind mAtg8s. Here, we identified LC3‐interacting regions (LIRs) in several SNAREs that broaden the landscape of the mAtg8‐SNARE interactions. We found that Syntaxin 16 (Stx16) and its cognate SNARE partners all have LIR motifs and bind mAtg8s. Knockout of Stx16 caused defects in lysosome biogenesis, whereas a Stx16 and Stx17 double knockout completely blocked autophagic flux and decreased mitophagy, pexophagy, xenophagy, and ribophagy. Mechanistic analyses revealed that mAtg8s and Stx16 control several properties of lysosomal compartments including their function as platforms for active mTOR. These findings reveal a broad direct interaction of mAtg8s with SNAREs with impact on membrane remodeling in eukaryotic cells and expand the roles of mAtg8s to lysosome biogenesis. Synopsis: While LC3B and other mammalian Atg8 (mAtg8) proteins induce autophagy, it remains unclear whether they have a direct role in autophagosome membrane remodelling. Here the authors show that mAtg8s bind to SNAP receptor (SNARE) proteins that contain LC3‐interacting regions (LIRs) and thereby control SNARE localization and autolysosomal biogenesis during autophagy. mAtg8s bind Syntaxin 16 and its cognate SNAREs, Vti1a and Syntaxin 6, via their LIRs. Double knockout of Syntaxin 16 and Syntaxin 17 inhibits diverse types of autophagy, including bulk autophagy, mitophagy, pexophagy and xenophagy. mAtg8 proteins regulate Syntaxin 16 localization and proper acidification of lysosomes. mAtg8s and Stx16 control recruitment of active mTOR to lysosomes. Abstract : Atg8 proteins bind to SNAP receptor (SNARE) proteins that contain LC3‐interacting regions and thereby control SNARE localization and autolysosomal biogenesis during autophagy in mammals.