DIPK2A promotes STX17-and VAMP7-mediated autophagosome-lysosome fusion by binding to VAMP7B
DIPK2A promotes STX17-and VAMP7-mediated autophagosome-lysosome fusion by binding to VAMP7B
复制标题
DIPK2A 通过与 VAMP7B 结合促进 STX17 和 VAMP7 介导的自噬体-溶酶体融合
DOI：
10.1080/15548627.2019.1637199
复制
发表时间：
2019-07-05
期刊：
影响因子：
13.3
通讯作者：
Chen，Jianguo
中科院分区：
文献类型：
--
作者：
Tian，Xiaoyu;Zheng，Pengli;Chen，Jianguo
自噬体和溶酶体融合是货物降解的重要巨自噬/自噬过程，而 SNARE 蛋白（包括 STX17、SNAP29、VAMP7 和 VAMP8）是该过程中的关键参与者。然而，人们对这一过程的精确调控方式知之甚少。在这里，我们发现 VAMP7B 是 R-SNARE 蛋白 VAMP7 的 SNARE 结构域破坏的亚型，与 SNARE 结构域功能亚型 VAMP7A 竞争结合 STX17 并抑制自噬体-溶酶体融合。此外，我们发现DIPK2A（一种晚期内体和溶酶体定位蛋白）与VAMP7B结合，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，其中不同亚型的 VAMP7 与 STX17 竞争及其受 DIPK2A 的调节。缩写： DIPK2A：不同的蛋白激酶结构域 2A； EEA1：早期内体抗原1； GOLGA2：高尔金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：线粒体编码的细胞色素c氧化酶II； PARP1：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：网织4； SNARE：SNAP 受体； SQSTM1/p62: 隔离体 1; STX17: 语法蛋白 17; TOMM20：线粒体外膜转位酶20； VAMP7：囊泡相关膜蛋白7； VAMP8：囊泡相关膜蛋白 8。
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.