Mammalian Atg8 proteins regulate lysosome and autolysosome biogenesis through SNARE s

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.

Membrane Location of Syntaxin-Binding Protein 1 Is Correlated with Poor Prognosis of Lung Adenocarcinoma

“…STXBP1 is previously reported to regulate the assemble of SNARE, which is the main machinery for secretion. However, the function of SNARE was reported in other physiological processes like the biogenesis of lysosome, autolysosome and exosome, and the dysregulation of these processes are widely reported in tumorigenesis and progression (Gu et al 2019). The intracellular location of STXBP1 was an indication of its function.…”

Syntaxin 16’s Newly Deciphered Roles in Autophagy

“…From the STX16 and STX17 single-and double-knockouts, it would appear that STX16 and STX17 share redundant functions in autophagosome-lysosome fusion, as loss of either has no significant phenotype while ablation of both almost completely abolished autophagic flux. In support of this notion, STX16, like STX17, could be recruited via its LIR to autophagosomes [68]. STX16 is a Qa-SNARE, and could therefore directly replace STX17 in fulfilling the stoichiometric requirement for a functional, fusion-mediating SNARE complex [87].…”

“…As it turns out, autophagosome biogenesis is not the only role STX16 has in autophagy, as recent work has also implicated it in a somewhat unexpected role of autolysosome formation [68]. On the basis of their earlier finding that STX17 harbors a LC3-interacting region (LIR) [72] for mammalian Atg8/LC3/GABARAP family members, and is thereby recruited onto autophagosomes, Deretic's group screened and found more SNAREs with LIRs [68]. Interestingly, the only R-SNARE identified in this regard is VAMP7 [68].…”

“…On the basis of their earlier finding that STX17 harbors a LC3-interacting region (LIR) [72] for mammalian Atg8/LC3/GABARAP family members, and is thereby recruited onto autophagosomes, Deretic's group screened and found more SNAREs with LIRs [68]. Interestingly, the only R-SNARE identified in this regard is VAMP7 [68]. Several Q-SNAREs with a wide range of cellular membrane distributions have LIRs, including ER-localized STX18 [73], plasma membrane-enriched STX3 and STX4 [74], as well as the Q-SNARE members of a SNARE complex at the TGN, STX6, STX16 and VTI1 [65].…”

“…However, a role for STX16, the mammalian homologue of Tlg2 [67], in autophagy has been unclear. Interestingly, recent findings now indicate that STX16 has a dual role, both in autophagosome formation [28], as well as in autolysosome biogenesis [68]. In the paragraphs below, these findings are discussed together with some mechanistic speculations on STX16's dual roles in autophagy.…”