Lin Yuchieh Jay, Huang Li-Ting, Ke Po-Yuan, Chen Guang-Chao
Institute of Biological Chemistry, Academia Sinica , Taipei, Taiwan.
Institute of Biochemical Sciences, College of Life Science, National Taiwan University , Taipei, Taiwan.
J Cell Biol. 2025 May 5;224(5). doi: 10.1083/jcb.202407014. Epub 2025 Mar 11.
The autophagy-lysosomal system comprises a highly dynamic and interconnected vesicular network that plays a central role in maintaining proteostasis and cellular homeostasis. In this study, we uncovered the deubiquitinating enzyme (DUB), dUsp45/USP45, as a key player in regulating autophagy and lysosomal activity in Drosophila and mammalian cells. Loss of dUsp45/USP45 results in autophagy activation and increased levels of V-ATPase to lysosomes, thus enhancing lysosomal acidification and function. Furthermore, we identified the actin-binding protein Coronin 1B (Coro1B) as a substrate of USP45. USP45 interacts with and deubiquitinates Coro1B, thereby stabilizing Coro1B levels. Notably, the ablation of USP45 or Coro1B promotes the formation of F-actin patches and the translocation of V-ATPase to lysosomes in an N-WASP-dependent manner. Additionally, we observed positive effects of dUsp45 depletion on extending lifespan and ameliorating polyglutamine (polyQ)-induced toxicity in Drosophila. Our findings highlight the important role of dUsp45/USP45 in regulating lysosomal function by modulating actin structures through Coro1B.
自噬-溶酶体系统由一个高度动态且相互连接的囊泡网络组成，该网络在维持蛋白质稳态和细胞内稳态中发挥核心作用。在本研究中，我们发现去泛素化酶（DUB）dUsp45/USP45是果蝇和哺乳动物细胞中调节自噬和溶酶体活性的关键因子。dUsp45/USP45的缺失导致自噬激活以及溶酶体上V-ATP酶水平升高，从而增强溶酶体酸化和功能。此外，我们鉴定出肌动蛋白结合蛋白冠蛋白1B（Coro1B）是USP45的底物。USP45与Coro1B相互作用并使其去泛素化，从而稳定Coro1B的水平。值得注意的是，USP45或Coro1B的缺失以N-WASP依赖的方式促进F-肌动蛋白斑块的形成以及V-ATP酶向溶酶体的转运。此外，我们观察到果蝇中dUsp45缺失对延长寿命和改善多聚谷氨酰胺（polyQ）诱导的毒性具有积极作用。我们的研究结果突出了dUsp45/USP45通过Coro1B调节肌动蛋白结构来调控溶酶体功能的重要作用。
