Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Cell Death Differ. 2023 Jan;30(1):94-110. doi: 10.1038/s41418-022-01048-2. Epub 2022 Aug 12.
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.
在后生动物中，内质网（ER）在细胞周期中经历广泛的重塑。内体分选复合物必需的运输（ESCRT）蛋白 CHMP7 在有丝分裂退出期间协调 ESCRT-III 依赖性核膜重构。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。我们表明，CHMP7 通过其 N 端膜结合结构域定位于多种细胞膜，包括 ER、线粒体相关膜（MAMs）和外线粒体膜（OMM）。CHMP7 通过其 C 端 CHMP 样结构域的α螺旋-1 和 α螺旋-2 之间的疏水相互作用在三向 ER 连接点和 ER-线粒体 MCS 中进行动态组装，这对于体内锚定不同的细胞器是必需的。此外，CHMP7 与 Atlastins（ATLs）一起介导三向 ER 连接点的形成。重要的是，CHMP7 还调节 ER-线粒体相互作用，其耗竭会影响线粒体分裂，而与 ESCRT 复合物无关。总之，我们的结果表明 CHMP7 在间期 ER 接触形成中起直接作用。
