Yue Wenkai, Zhang Kai, Jiang Mingsheng, Long Wenjing, Cui Jihong, Li Yunxia, Zhang Yaoyang, Li Ang, Fang Yanshan
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Life Med. 2023 Nov 4;2(5):lnad040. doi: 10.1093/lifemedi/lnad040. eCollection 2023 Oct.
Sterile alpha and Toll/interleukin 1 receptor motif-containing protein 1 (SARM1) is regarded as a key protein and a central executor of the self-destruction of injured axons. To identify novel molecular players and understand the mechanisms regulating SARM1 function, we investigated the interactome of SARM1 by proximity labeling and proteomic profiling. Among the SARM1-associated proteins, we uncovered that overexpression (OE) of ubiquitin-specific peptidase 13 (USP13) delayed injury-induced axon degeneration. OE of an enzyme-dead USP13 failed to protect injured axons, indicating that the deubiquitinase activity of USP13 was required for its axonal protective effect. Further investigation revealed that USP13 deubiquitinated SARM1, which increased the inhibitory interaction between the N-terminal armadillo repeat motif (ARM) and C-terminal Toll/interleukin-1 receptor (TIR) domains of the SARM1 protein, thereby suppressing SARM1 activation in axon injury. Collectively, these findings suggest that increase of USP13 activity enhances the self-inhibition of SARM1, which may provide a strategy to mitigate axon degeneration in injury and disease.
含无菌α和Toll/白细胞介素1受体基序蛋白1（SARM1）被视为关键蛋白，是受损轴突自我破坏的核心执行者。为了鉴定新的分子参与者并了解调节SARM1功能的机制，我们通过邻近标记和蛋白质组分析研究了SARM1的相互作用组。在与SARM1相关的蛋白质中，我们发现泛素特异性肽酶13（USP13）的过表达（OE）延迟了损伤诱导的轴突变性。酶失活的USP13的过表达未能保护受损轴突，表明USP13的去泛素酶活性是其轴突保护作用所必需的。进一步研究表明，USP13使SARM1去泛素化，这增加了SARM1蛋白N端犰狳重复基序（ARM）和C端Toll/白细胞介素-1受体（TIR）结构域之间的抑制性相互作用，从而抑制轴突损伤中SARM1的激活。总的来说，这些发现表明USP13活性的增加增强了SARM1的自我抑制，这可能为减轻损伤和疾病中的轴突变性提供一种策略。
