Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing, China.
Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University, Lanzhou, China.
Autophagy. 2020 May;16(5):797-810. doi: 10.1080/15548627.2019.1637199. Epub 2019 Jul 4.
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.: 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.
自噬体与溶酶体融合是货物降解的重要巨自噬/自噬过程，SNARE 蛋白，包括 STX17、SNAP29、VAMP7 和 VAMP8，是该过程的关键参与者。然而，这个过程是如何被精确调控的还知之甚少。在这里，我们发现 SNARE 结构域缺失的 R-SNARE 蛋白 VAMP7 的异构体 VAMP7B 与具有 SNARE 结构域功能的异构体 VAMP7A 竞争与 STX17 结合，从而抑制自噬体-溶酶体融合。此外，我们发现定位于晚期内体和溶酶体的蛋白 DIPK2A 与 VAMP7B 结合，从而抑制 VAMP7B 与 STX17 的相互作用，并增强 STX17 与 VAMP7A 的结合，从而增强自噬体-溶酶体融合。此外，DIPK2A 参与线粒体蛋白的自噬降解并减轻细胞凋亡。因此，我们揭示了自噬体-溶酶体融合的一个新方面，其中 VAMP7 的不同异构体与 STX17 竞争，并且它们的调节由 DIPK2A 介导。DIPK2A：有差异的蛋白激酶结构域 2A；EEA1：早期内体抗原 1；GOLGA2：高尔基体蛋白 A2；LAMP1：溶酶体相关膜蛋白 1；MAP1LC3B/LC3：微管相关蛋白 1 轻链 3β；MFN2：线粒体融合蛋白 2；MT-CO2：线粒体编码细胞色素 c 氧化酶 II；PARP1：多聚（ADP-核糖）聚合酶 1；PRKN：Parkin RBR E3 泛素蛋白连接酶；RAB5A：RAB5A，RAS 癌基因家族成员；RAB7A：RAB7A，RAS 癌基因家族成员；REEP：受体辅助蛋白；RTN4：网蛋白 4；SNARE：SNAP 受体；SQSTM1/p62：自噬相关蛋白 1；STX17：突触融合蛋白 17；TOMM20：外线粒体膜转位酶 20；VAMP7：囊泡相关膜蛋白 7；VAMP8：囊泡相关膜蛋白 8。
