Georges Anna, Gros Philippe, Fodil Nassima
Department of Biochemistry, McGill University, Montreal, QC, Canada.
McGill University Research Centre on Complex Traits, McGill University, Montreal, QC, Canada.
Genes Immun. 2021 May;22(1):12-23. doi: 10.1038/s41435-021-00125-9. Epub 2021 Apr 6.
The covalent post-translational modification of proteins by ubiquitination not only influences protein stability and half-life, but also several aspects of protein function including enzymatic activity, sub-cellular localization, and interactions with binding partners. Protein ubiquitination status is determined by the action of large families of ubiquitin ligases and deubiquitinases, whose combined activities regulate many physiological and cellular pathways. The Ubiquitin Specific Protease (USP) family is one of 8 subfamilies of deubiquitinating enzymes composed of more than 50 members. Recent studies have shown that USP15 plays a critical role in regulating many aspects of immune and inflammatory function of leukocytes in response to a broad range of infectious and autoimmune insults and following tissue damage. USP15 regulated pathways reviewed herein include TLR signaling, RIG-I signaling, NF-kB, and IRF3/IRF7-dependent transcription for production of pro-inflammatory cytokines and type I interferons. In addition, USP15 has been found to regulate pathways implicated in tumor onset and progression such as p53, and TGF-β signaling, but also influences the leukocytes-determined immune and inflammatory microenvironment of tumors to affect progression and outcome. Hereby reviewed are recent studies of USP15 in model cell lines in vitro, and in mutant mice in vivo with reference to available human clinical datasets.
蛋白质的泛素化共价翻译后修饰不仅影响蛋白质的稳定性和半衰期，还影响蛋白质功能的多个方面，包括酶活性、亚细胞定位以及与结合伴侣的相互作用。蛋白质的泛素化状态由泛素连接酶和去泛素化酶大家族的作用决定，它们的联合活性调节许多生理和细胞途径。泛素特异性蛋白酶（USP）家族是由50多个成员组成的去泛素化酶的8个亚家族之一。最近的研究表明，USP15在调节白细胞免疫和炎症功能的许多方面发挥关键作用，这些功能涉及对广泛的感染和自身免疫损伤以及组织损伤的反应。本文综述的USP15调节途径包括Toll样受体（TLR）信号传导、维甲酸诱导基因I（RIG-I）信号传导、核因子κB（NF-κB）以及依赖于干扰素调节因子3/干扰素调节因子7（IRF3/IRF7）的转录，以产生促炎细胞因子和I型干扰素。此外，已发现USP15调节与肿瘤发生和进展相关的途径，如p53和转化生长因子-β（TGF-β）信号传导，而且还影响由白细胞决定的肿瘤免疫和炎症微环境，从而影响肿瘤的进展和结局。本文参考现有的人类临床数据集，综述了最近在体外模型细胞系和体内突变小鼠中对USP15的研究。
