College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
Department of Rheumatology and Immunology, Jinling Hospital, Affiliated Hosptial of Medical School, Nanjing University, Nanjing, 210002, China.
Cell Mol Life Sci. 2023 Apr 22;80(5):129. doi: 10.1007/s00018-023-04778-9.
Ufmylation is a recently identified small ubiquitin-like modification, whose biological function and relevant cellular targets are poorly understood. Here we present evidence of a neuroprotective role for Ufmylation involving Autophagy-related gene 9 (Atg9) during Drosophila aging. The Ufm1 system ensures the health of aged neurons via Atg9 by coordinating autophagy and mTORC1, and maintaining mitochondrial homeostasis and JNK (c-Jun N-terminal kinase) activity. Neuron-specific expression of Atg9 suppresses the age-associated movement defect and lethality caused by loss of Ufmylation. Furthermore, Atg9 is identified as a conserved target of Ufm1 conjugation mediated by Ddrgk1, a critical regulator of Ufmylation. Mammalian Ddrgk1 was shown to be indispensable for the stability of endogenous Atg9A protein in mouse embryonic fibroblast (MEF) cells. Taken together, our findings might have important implications for neurodegenerative diseases in mammals.
泛素化是一种新发现的小泛素样修饰，其生物学功能和相关细胞靶点尚未完全了解。在这里，我们提出了泛素化在果蝇衰老过程中通过自噬相关基因 9（Atg9）发挥神经保护作用的证据。Ufm1 系统通过协调自噬和 mTORC1，维持线粒体稳态和 JNK（c-Jun N-末端激酶）活性，确保衰老神经元的健康。神经元特异性表达 Atg9 可抑制由泛素化缺失引起的与年龄相关的运动缺陷和致死性。此外，Atg9 被鉴定为由 Ddrgk1 介导的 Ufm1 缀合的保守靶标，Ddrgk1 是泛素化的关键调节因子。研究表明，Ddrgk1 在小鼠胚胎成纤维细胞（MEF）中对内源性 Atg9A 蛋白的稳定性是不可或缺的。总之，我们的发现可能对哺乳动物的神经退行性疾病具有重要意义。
