Yu Jian-Shuai, Huang Tao, Zhang Yu, Mao Xin-Tao, Huang Ling-Jie, Li Yi-Ning, Wu Ting-Ting, Zhong Jiang-Yan, Cao Qian, Li Yi-Yuan, Jin Jin
MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China.
Sci Adv. 2021 Jan 13;7(3). doi: 10.1126/sciadv.abc4009. Print 2021 Jan.
The classic NF-κB pathway plays crucial roles in various immune responses and inflammatory diseases. Its key kinase, IKKβ, participates in a variety of pathological and physiological processes by selectively recognizing its downstream substrates, including p105, p65, and IκBα, but the specific mechanisms of these substrates are unclear. Hyperactivation of one of the substrates, p105, is closely related to the onset of inflammatory bowel disease (IBD) in -deficient mice. In this study, we found that IKKβ ubiquitination on lysine-238 was substantially increased during inflammation. Using mass spectrometry, we identified USP16 as an essential regulator of the IKKβ ubiquitination level that selectively affected p105 phosphorylation without directly affecting p65 or IκBα phosphorylation. Furthermore, USP16 was highly expressed in colon macrophages in patients with IBD, and myeloid-conditional USP16-knockout mice exhibited reduced IBD severity. Our study provides a new theoretical basis for IBD pathogenesis and targeted precision intervention therapy.
经典的核因子κB（NF-κB）信号通路在多种免疫反应和炎症性疾病中发挥着关键作用。其关键激酶IKKβ通过选择性识别包括p105、p65和IκBα在内的下游底物，参与多种病理和生理过程，但这些底物的具体机制尚不清楚。其中一种底物p105的过度激活与T细胞缺陷小鼠炎症性肠病（IBD）的发病密切相关。在本研究中，我们发现炎症期间赖氨酸-238位点的IKKβ泛素化显著增加。通过质谱分析，我们确定USP16是IKKβ泛素化水平的关键调节因子，它选择性地影响p105磷酸化，而不直接影响p65或IκBα磷酸化。此外，USP16在IBD患者的结肠巨噬细胞中高表达，髓系条件性USP16基因敲除小鼠的IBD严重程度降低。我们的研究为IBD的发病机制和靶向精准干预治疗提供了新的理论依据。
