TRIM14 Promotes Noncanonical NF-κB Activation by Modulating p100/p52 Stability via Selective Autophagy
TRIM14 Promotes Noncanonical NF-κB Activation by Modulating p100/p52 Stability via Selective Autophagy
复制标题
TRIM14 通过选择性自噬调节 p100/p52 稳定性，促进非经典 NF-kappa B 激活
DOI：
10.1002/advs.201901261
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发表时间：
2019-11-11
期刊：
影响因子：
15.1
通讯作者：
Cui, Jun
中科院分区：
文献类型：
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作者：
Chen, Meixin;Zhao, Zhiyao;Cui, Jun
非规范nf - κ B信号通路在多种生物学功能中发挥关键作用，包括慢性炎症和肿瘤发生。非典型NF-kappa B信号的激活在很大程度上依赖于NF-kappa B家族成员p100/p52的丰度和加工。在这里，TRIM14被鉴定为非典型NF-kappa B信号通路的一种新的正调节因子。TRIM14在体外和体内通过靶向p100/p52促进非典型NF-kappa B的激活。此外，一项机制研究表明，TRIM14招募去泛素酶USP14，在多个位点切割p100/p52的k63连接的泛素链，从而阻止p100/p52从货物受体p62介导的自噬降解。小鼠TRIM14缺乏显著损害非规范nf - κ b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，这些发现确定了TRIM14-USP14轴作为控制非规范NF-kappa B信号的关键检查点，并强调了自噬和先天免疫之间的串扰。
The noncanonical NF-kappa B signaling pathway plays a critical role in a variety of biological functions including chronic inflammation and tumorigenesis. Activation of noncanonical NF-kappa B signaling largely relies on the abundance as well as the processing of the NF-kappa B family member p100/p52. Here, TRIM14 is identified as a novel positive regulator of the noncanonical NF-kappa B signaling pathway. TRIM14 promotes noncanonical NF-kappa B 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-kappa B-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-kappa B signaling and highlight the crosstalk between autophagy and innate immunity.