Wang Jie, Xia Jia, Su Juncheng, Cao Ziyi, Yang Wen, Zhang Peng, Xu Yingjie
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
Department of Pharmacology and Chemical Biology, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
J Proteome Res. 2025 Jun 6;24(6):2832-2845. doi: 10.1021/acs.jproteome.4c01111. Epub 2025 Apr 27.
Proteins are constantly damaged by intracellular and extracellular factors, particularly under stress conditions, leading to an accumulation of modified proteins such as isoaspartate (isoD), which is linked to aging and various diseases. The repair enzyme PCMT1 (protein-l-isoaspartate -methyltransferase) specifically restores isoD residues to aspartate, preventing abnormal protein functions. Despite its importance, its role in non-neural tissues remains underexplored. This study employed isoD-proteomics, global proteomics, and transcriptomics on knockout (KO) and wild-type (WT) mice, revealing significant gene and protein changes in various KO tissues, enriched in extracellular and membrane-related categories, highlighting genome-proteome correlations. IsoD-carrying proteins were increased in KO tissues, predominantly consisting of long-lived proteins. Additionally, the proteomic analysis of PCMT1-overexpressing cells identified interacting proteins mainly in extracellular and membrane-related categories. These findings revealed both tissue-specific and shared roles of PCMT1, emphasizing its importance in maintaining protein integrity under physiological and stress conditions while also uncovering an unexpected extracellular function of PCMT1.
蛋白质会不断受到细胞内和细胞外因素的损害，尤其是在应激条件下，导致诸如异天冬氨酸（isoD）等修饰蛋白的积累，而异天冬氨酸与衰老和各种疾病有关。修复酶PCMT1（蛋白质 - l - 异天冬氨酸 - 甲基转移酶）能将异天冬氨酸残基特异性地恢复为天冬氨酸，防止蛋白质功能异常。尽管其很重要，但其在非神经组织中的作用仍未得到充分研究。本研究对基因敲除（KO）小鼠和野生型（WT）小鼠进行了异天冬氨酸蛋白质组学、全局蛋白质组学和转录组学研究，揭示了各种基因敲除组织中显著的基因和蛋白质变化，这些变化主要集中在细胞外和膜相关类别中，突出了基因组 - 蛋白质组的相关性。基因敲除组织中携带异天冬氨酸的蛋白质增加，主要由长寿蛋白组成。此外，对过表达PCMT1的细胞进行蛋白质组学分析，确定相互作用的蛋白质主要集中在细胞外和膜相关类别中。这些发现揭示了PCMT1在组织特异性和共同方面的作用，强调了其在生理和应激条件下维持蛋白质完整性的重要性，同时也揭示了PCMT1意想不到的细胞外功能。
