Chen Meixin, Zhao Zhiyao, Meng Qingcai, Liang Puping, Su Zexiong, Wu Yaoxing, Huang Junjiu, Cui Jun
State Key Laboratory of Oncology in South China MOE Key Laboratory of Gene Function and Regulation School of Life Sciences Sun Yat-Sen University Guangzhou Guangdong 510006 China.
Department of Internal Medicine Guangzhou Institute of Pediatrics Guangzhou Women and Children's Medical Center Guangzhou Guangdong 510623 China.
Adv Sci (Weinh). 2019 Nov 11;7(1):1901261. doi: 10.1002/advs.201901261. eCollection 2020 Jan.
The noncanonical NF-κB signaling pathway plays a critical role in a variety of biological functions including chronic inflammation and tumorigenesis. Activation of noncanonical NF-κB signaling largely relies on the abundance as well as the processing of the NF-κB family member p100/p52. Here, TRIM14 is identified as a novel positive regulator of the noncanonical NF-κB signaling pathway. TRIM14 promotes noncanonical NF-κB activation by targeting p100/p52 in vitro and in vivo. Furthermore, a mechanistic study shows that TRIM14 recruits deubiquitinase USP14 to cleave the K63-linked ubiquitin chains of p100/p52 at multiple sites, thereby preventing p100/p52 from cargo receptor p62-mediated autophagic degradation. TRIM14 deficiency in mice significantly impairs noncanonical NF-κB-mediated inflammatory responses as well as acute colitis and colitis-associated colon cancer development. Taken together, these findings establish the TRIM14-USP14 axis as a crucial checkpoint that controls noncanonical NF-κB signaling and highlight the crosstalk between autophagy and innate immunity.
非经典NF-κB信号通路在包括慢性炎症和肿瘤发生在内的多种生物学功能中起关键作用。非经典NF-κB信号通路的激活很大程度上依赖于NF-κB家族成员p100/p52的丰度及其加工过程。在此，TRIM14被鉴定为非经典NF-κB信号通路的一种新型正调控因子。TRIM14在体外和体内通过靶向p100/p52促进非经典NF-κB的激活。此外，一项机制研究表明，TRIM14招募去泛素化酶USP14在多个位点切割p100/p52的K63连接的泛素链，从而防止p100/p52被货物受体p62介导的自噬降解。小鼠中TRIM14的缺乏显著损害非经典NF-κB介导的炎症反应以及急性结肠炎和结肠炎相关结肠癌的发展。综上所述，这些发现确立了TRIM14-USP14轴作为控制非经典NF-κB信号通路的关键检查点，并突出了自噬与先天免疫之间的相互作用。
