Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Osnabrück University, Department of Biology/Chemistry, Biochemistry section, Osnabrück, Germany.
Nat Commun. 2023 Oct 11;14(1):6360. doi: 10.1038/s41467-023-42003-0.
The multi-subunit homotypic fusion and vacuole protein sorting (HOPS) membrane-tethering complex is required for autophagosome-lysosome fusion in mammals, yet reconstituting the mammalian HOPS complex remains a challenge. Here we propose a "hook-up" model for mammalian HOPS complex assembly, which requires two HOPS sub-complexes docking on membranes via membrane-associated Rabs. We identify Rab39A as a key small GTPase that recruits HOPS onto autophagic vesicles. Proper pairing with Rab2 and Rab39A enables HOPS complex assembly between proteoliposomes for its tethering function, facilitating efficient membrane fusion. GTP loading of Rab39A is important for the recruitment of HOPS to autophagic membranes. Activation of Rab39A is catalyzed by C9orf72, a guanine exchange factor associated with amyotrophic lateral sclerosis and familial frontotemporal dementia. Constitutive activation of Rab39A can rescue autophagy defects caused by C9orf72 depletion. These results therefore reveal a crucial role for the C9orf72-Rab39A-HOPS axis in autophagosome-lysosome fusion.
多亚基同源融合和液泡蛋白分选（HOPS）膜连接复合物对于哺乳动物中的自噬体-溶酶体融合是必需的，但重组哺乳动物 HOPS 复合物仍然是一个挑战。在这里，我们提出了一种用于哺乳动物 HOPS 复合物组装的“钩接”模型，该模型需要两个 HOPS 亚复合物通过膜相关 Rab 停靠在膜上。我们确定 Rab39A 是一种关键的小 GTPase，可将 HOPS 募集到自噬体囊泡上。与 Rab2 和 Rab39A 的正确配对使 HOPS 复合物在蛋白脂质体之间组装，从而促进有效的膜融合。Rab39A 的 GTP 加载对于 HOPS 募集到自噬膜是重要的。Rab39A 的激活由 C9orf72 催化，C9orf72 是一种与肌萎缩侧索硬化症和家族性额颞叶痴呆相关的鸟嘌呤交换因子。Rab39A 的组成性激活可以挽救由 C9orf72 耗竭引起的自噬缺陷。因此，这些结果揭示了 C9orf72-Rab39A-HOPS 轴在自噬体-溶酶体融合中的关键作用。
Zotero 插件
