DIPK2A promotes STX17- and VAMP7-mediated autophagosome-lysosome fusion by binding to VAMP7B

Autophagy. 2020 May;16(5):797-810. doi: 10.1080/15548627.2019.1637199. Epub 2019 Jul 4.

Abstract

Autophagosome and lysosome fusion is an important macroautophagy/autophagy process for cargo degradation, and SNARE proteins, including STX17, SNAP29, VAMP7 and VAMP8, are key players in this process. However, the manner in which this process is precisely regulated is poorly understood. Here, we show that VAMP7B, a SNARE domain-disrupted isoform of R-SNARE protein VAMP7, competes with SNARE domain functional isoform VAMP7A to bind to STX17 and inhibits autophagosome-lysosome fusion. Moreover, we show that DIPK2A, a late endosome- and lysosome-localized protein, binds to VAMP7B, which inhibits the interaction of VAMP7B with STX17 and enhances the binding of STX17 to VAMP7A, thus enhancing autophagosome-lysosome fusion. Furthermore, DIPK2A participates in autophagic degradation of mitochondria proteins and alleviates apoptosis. Thus, we reveal a new aspect of autophagosome-lysosome fusion in which different isoforms of VAMP7 compete with STX17 and their regulation by DIPK2A.Abbreviations: DIPK2A: divergent protein kinase domain 2A; EEA1: early endosome antigen 1; GOLGA2: golgin A2; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MT-CO2: mitochondrially encoded cytochrome c oxidase II; PARP1: poly(ADP-ribose) polymerase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RAB5A: RAB5A, member RAS oncogene family; RAB7A: RAB7A, member RAS oncogene family; REEP: receptor accessory protein; RTN4: reticulon 4; SNARE: SNAP receptor; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TOMM20: translocase of outer mitochondrial membrane 20; VAMP7: vesicle associated membrane protein 7; VAMP8: vesicle associated membrane protein 8.

Keywords: Autophagosome-lysosome fusion; DIPK2A; STX17; VAMP7; autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Autophagosomes / metabolism*
  • Autophagy / physiology
  • Endosomes / metabolism
  • Humans
  • Lysosomes / metabolism*
  • Macroautophagy / physiology
  • Membrane Proteins / metabolism*
  • Qa-SNARE Proteins / metabolism*
  • R-SNARE Proteins / metabolism*

Substances

  • Adaptor Proteins, Vesicular Transport
  • DIPK2A protein, human
  • Membrane Proteins
  • Qa-SNARE Proteins
  • R-SNARE Proteins
  • STX17 protein, human
  • VAMP7 protein, human
  • VAMP8 protein, human

Grants and funding

This work was supported by the National Natural Science Foundation of China (NSFC) (grants 31871353 and 31671392) and the National Key Research and Development Program of China, Stem Cell and Translational Research (2016YFA0100501)