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Dev Cell. 2019 Feb 27. pii: S1534-5807(19)30055-3. doi: 10.1016/j.devcel.2019.01.027. [Epub ahead of print]

Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation.

Author information

1
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.
2
Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø, The Arctic University of Norway, Tromsø 9037, Norway.
3
Department of Molecular Cell Biology, Centre for Cancer Biomedicine, University of Oslo and Institute for Cancer Research, The Norwegian Radium Hospital, Oslo 0379, Norway.
4
Departments of Physics and Astronomy, University of New Mexico, Albuquerque, NM 87131, USA.
5
Department of Biosciences IBV Mass Spectrometry and Proteomics Unit, University of Oslo, Oslo 0371, Norway.
6
Cell Signaling Technology, Danvers, MA 01923, USA.
7
Signalling Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
8
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. Electronic address: vderetic@salud.unm.edu.

Abstract

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 ATG13+FIP200+ mammalian pre-autophagosomal structure (mPAS) in response to induction of autophagy. TBK1 phosphorylates Stx17 at S202. During autophagy induction, Stx17pS202 transfers from the Golgi, where its steady-state pools localize, to the ATG13+FIP200+ mPAS. Stx17pS202 was in complexes with ATG13 and FIP200, whereas its non-phosphorylatable mutant Stx17S202A 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 Stx17pS202 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.

KEYWORDS:

TBK1; ULK1; autophagy; pre-autophagosomal structure

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