Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation

Kumar, Suresh; Gu, Yuexi; Abudu, Yakubu Princely; Bruun, Jack‐Ansgar; Jain, Ashish; Farzam, Farzin; Mudd, Michal H.; Anonsen, Jan Haug; Rusten, Tor Erik; Kasof, Gary M.; Ktistakis, Nicholas T.; Lidke, Keith A.; Johansen, Terje; Deretić, Vojo

doi:10.1016/j.devcel.2019.01.027

Cited by 106 publications

(103 citation statements)

References 67 publications

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“…Thus, redundant, complementary or synergistic SNARE-driven fusion and regulatory events may be at work during autolysosomal fusion. We have recently shown that Stx17 interacts via its LIR motif with mAtg8s, which functions in Stx17's recruitment to autophagosomes (Kumar et al, 2018), and that TBK1-phosphorylated Stx17 plays a role in autophagy initiation (Kumar et al, 2019), in keeping with studies by others (Hamasaki et al, 2013;Arasaki et al, 2015Arasaki et al, , 2018. Thus, Stx17 contributes to the autophagy pathway at several stages from initiation to maturation.…”

Section: Introductionsupporting

confidence: 81%

“…At the autophagosome-lysosome fusion stage, an initially identified SNARE was the Qa-SNARE Stx17, forming complexes with Qbc-SNARE SNAP29 and R-SNARE VAMP8 (Itakura et al, 2012;Takats et al, 2013;Guo et al, 2014;Diao et al, 2015;Wang et al, 2016). We have recently shown that Stx17 interacts via its LIR motif with mAtg8s, which functions in Stx17's recruitment to autophagosomes (Kumar et al, 2018), and that TBK1-phosphorylated Stx17 plays a role in autophagy initiation (Kumar et al, 2019), in keeping with studies by others (Hamasaki et al, 2013;Arasaki et al, 2015Arasaki et al, , 2018. Thus, redundant, complementary or synergistic SNARE-driven fusion and regulatory events may be at work during autolysosomal fusion.…”

Section: Introductionmentioning

confidence: 99%

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Mammalian Atg8 proteins regulate lysosome and autolysosome biogenesis through SNARE s

Abudu

Kumar

et al. 2019

The EMBO Journal

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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.

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Section: Introductionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Mammalian Atg8 proteins regulate lysosome and autolysosome biogenesis through SNARE s

Abudu

Kumar

et al. 2019

The EMBO Journal

Self Cite

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“…From another perspective, having a Q-SNARE (STX16) and an R-SNARE (VAMP7) at both the beginning and the end point of the autophagy process could be a way to coordinately regulate autophagosome formation and its eventual lysosomal fusion. STX17 has likewise been shown to regulate initiation of autophagy through its phosphorylation by TANK-binding kinase 1 (TBK1) [58]. Such coordinated or multivalent regulation of autophagy has also been demonstrated for the small GTPase RAB2, which was recently shown to regulate both autophagosome and autolysosome formation [89].…”

Section: New Perspectivesmentioning

confidence: 93%

“…Its autophagosomal recruitment is also mediated by interactions with immunity-related GTPase family M protein (IGRM) and LC3 [57]. Interestingly, STX17 has also been implicated in phagophore closure [7] and in regulating autophagy initiation [58]. The longin SNARE Ykt6 has also been recently implicated in autophagosome-lysosome fusion, although its mode of action remains to be precisely determined [59][60][61][62].…”

Section: Introductionmentioning

confidence: 99%

Syntaxin 16’s Newly Deciphered Roles in Autophagy

Tang

2019

Cells

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Syntaxin 16, a Qa-SNARE (soluble N-ethylmaleimide-sensitive factor activating protein receptor), is involved in a number of membrane-trafficking activities, particularly transport processes at the trans-Golgi network (TGN). Recent works have now implicated syntaxin 16 in the autophagy process. In fact, syntaxin 16 appears to have dual roles, firstly in facilitating the transport of ATG9a-containing vesicles to growing autophagosomes, and secondly in autolysosome formation. The former involves a putative SNARE complex between syntaxin 16, VAMP7 and SNAP-47. The latter occurs via syntaxin 16’s recruitment by Atg8/LC3/GABARAP family proteins to autophagosomes and endo-lysosomes, where syntaxin 16 may act in a manner that bears functional redundancy with the canonical autophagosome Qa-SNARE syntaxin 17. Here, I discuss these recent findings and speculate on the mechanistic aspects of syntaxin 16’s newly found role in autophagy.

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“…TBK1 also plays important roles in autophagy regulation, at least some of which are independent of STING. For instance, TBK1-mediated phosphorylation of syntaxin 17 is required for the earliest steps of autophagosome formation (Kumar et al, 2019) and TBK1 also has a role in allowing for autophagic maturation (Pilli et al, 2012). These activities may be in addition to or in conjunction with TBK1's roles in promoting autophagic cargo selectivity through actions on autophagy receptors p62, NDP52, and optineurin (Pilli et al, 2012;Richter et al, 2016;Vargas et al, 2019).…”

Section: Actions Of Trims On Autophagy-regulating Signaling Pathwaysmentioning

confidence: 99%

The Tripartite Nexus: Autophagy, Cancer, and Tripartite Motif-Containing Protein Family Members

2020

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Autophagy is a cellular degradative process that has multiple important actions in cancer. Autophagy modulation is under consideration as a promising new approach to cancer therapy. However, complete autophagy dysregulation is likely to have substantial undesirable side effects. Thus, more targeted approaches to autophagy modulation may prove clinically beneficial. One potential avenue to achieving this goal is to focus on the actions of tripartite motif-containing protein family members (TRIMs). TRIMs have key roles in an array of cellular processes, and their dysregulation has been extensively linked to cancer risk and prognosis. As detailed here, emerging data shows that TRIMs can play important yet context-dependent roles in controlling autophagy and in the selective targeting of autophagic substrates. This review covers how the autophagyrelated actions of TRIM proteins contribute to cancer and the possibility of targeting TRIMdirected autophagy in cancer therapy.

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Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation

Cited by 106 publications

References 67 publications

Mammalian Atg8 proteins regulate lysosome and autolysosome biogenesis through SNARE s

Mammalian Atg8 proteins regulate lysosome and autolysosome biogenesis through SNARE s

Syntaxin 16’s Newly Deciphered Roles in Autophagy

The Tripartite Nexus: Autophagy, Cancer, and Tripartite Motif-Containing Protein Family Members

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