TBK1 对突触融合蛋白 17 的磷酸化控制自噬的起始。
Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation.
机构信息
Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø, The Arctic University of Norway, Tromsø 9037, Norway.
出版信息
Dev Cell. 2019 Apr 8;49(1):130-144.e6. doi: 10.1016/j.devcel.2019.01.027. Epub 2019 Feb 28.
Syntaxin 17 (Stx17) has been implicated in autophagosome-lysosome fusion. Here, we report that Stx17 functions in assembly of protein complexes during autophagy initiation. Stx17 is phosphorylated by TBK1 whereby phospho-Stx17 controls the formation of the ATG13FIP200 mammalian pre-autophagosomal structure (mPAS) in response to induction of autophagy. TBK1 phosphorylates Stx17 at S202. During autophagy induction, Stx17 transfers from the Golgi, where its steady-state pools localize, to the ATG13FIP200 mPAS. Stx17 was in complexes with ATG13 and FIP200, whereas its non-phosphorylatable mutant Stx17 was not. Stx17 or TBK1 knockouts blocked ATG13 and FIP200 puncta formation. Stx17 or TBK1 knockouts reduced the formation of ATG13 protein complexes with FIP200 and ULK1. Endogenous Stx17 colocalized with LC3B following induction of autophagy. Stx17 knockout diminished LC3 response and reduced sequestration of the prototypical bulk autophagy cargo lactate dehydrogenase. We conclude that Stx17 is a TBK1 substrate and that together they orchestrate assembly of mPAS.
突触融合蛋白 17（Stx17）参与了自噬体-溶酶体融合。在这里，我们报告 Stx17 在自噬体发生过程中参与蛋白质复合物的组装。Stx17 被 TBK1 磷酸化，磷酸化的 Stx17 控制着 ATG13FIP200 哺乳动物前自噬体结构（mPAS）的形成，以响应自噬的诱导。TBK1 在 S202 处磷酸化 Stx17。在自噬诱导过程中，Stx17 从其稳定状态池所在的高尔基体转移到 ATG13FIP200 mPAS。Stx17 与 ATG13 和 FIP200 形成复合物，而其不可磷酸化的突变体 Stx17 则没有。Stx17 或 TBK1 敲除阻止了 ATG13 和 FIP200 点状结构的形成。Stx17 或 TBK1 敲除减少了 ATG13 与 FIP200 和 ULK1 的蛋白复合物的形成。内源性 Stx17 在自噬诱导后与 LC3B 共定位。Stx17 敲除减少了 LC3 的反应，并减少了典型的大体积自噬货物乳酸脱氢酶的隔离。我们的结论是，Stx17 是 TBK1 的底物，它们共同协调 mPAS 的组装。
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