Cell Death and Differentiation ( IF 12.4 ) Pub Date : 2022-08-12 , DOI: 10.1038/s41418-022-01048-2 Qingzhu Chu 1 , Jingru Wang 1 , Yuanjiao Du 1 , Tiantian Zhou 1 , Anbing Shi 1, 2 , Juan Xiong 3 , Wei-Ke Ji 1, 2 , Lin Deng 4
In metazoans the endoplasmic reticulum (ER) undergoes extensive remodeling during the cell cycle. The endosomal sorting complexes required for transport (ESCRT) protein CHMP7 coordinates ESCRT-III dependent nuclear envelope reformation during mitotic exit. However, potential roles of ER-associated CHMP7 at non-mitotic stages remain unclear. Here we discovered a new role of CHMP7 in mediating three-way ER and ER-mitochondrial membrane contact sites (MCSs). We showed that CHMP7 localizes to multiple cellular membranes including the ER, mitochondrial-associated membranes (MAMs) and the outer mitochondrial membrane (OMM) via its N-terminal membrane-binding domain. CHMP7 undergoes dynamic assembly at three-way ER junctions and ER-mitochondrial MCSs through hydrophobic interactions among α helix-1 and α helix-2 of the C-terminal CHMP-like domain, which was required for tethering different organelles in vivo. Furthermore, CHMP7 mediates the formation of three-way ER junctions in parallel with Atlastins (ATLs). Importantly, CHMP7 also regulates ER-mitochondrial interactions and its depletion affects mitochondrial division independently of ESCRT complex. Taken together, our results suggest a direct role of CHMP7 in the formation of the ER contacts in interphase.
中文翻译:
寡聚 CHMP7 介导三向 ER 连接和 ER-线粒体相互作用
在后生动物中,内质网 (ER) 在细胞周期中经历了广泛的重塑。运输 (ESCRT) 蛋白 CHMP7 所需的内体分选复合物在有丝分裂退出期间协调 ESCRT-III 依赖性核膜改造。然而,ER 相关 CHMP7 在非有丝分裂阶段的潜在作用仍不清楚。在这里,我们发现了 CHMP7 在介导三向 ER 和 ER-线粒体膜接触位点 (MCS) 中的新作用。我们发现 CHMP7 通过其 N 端膜结合域定位于多种细胞膜,包括 ER、线粒体相关膜 (MAM) 和线粒体外膜 (OMM)。CHMP7 通过 C 端 CHMP 样结构域的 α helix-1 和 α helix-2 之间的疏水相互作用在三向 ER 连接和 ER-线粒体 MCS 处进行动态组装,这是在体内连接不同细胞器所必需的。此外,CHMP7 介导了与 Atlastins (ATL) 并行的三向 ER 连接的形成。重要的是,CHMP7 还调节 ER-线粒体相互作用,其耗竭影响线粒体分裂,与 ESCRT 复合物无关。总之,我们的结果表明 CHMP7 在间期 ER 接触的形成中起直接作用。