RT Journal Article
SR Electronic
T1 Substrate-specific recognition of IKKs mediated by USP16 facilitates autoimmune inflammation
JF Science Advances
JO Sci Adv
FD American Association for the Advancement of Science
SP eabc4009
DO 10.1126/sciadv.abc4009
VO 7
IS 3
A1 Yu, Jian-shuai
A1 Huang, Tao
A1 Zhang, Yu
A1 Mao, Xin-tao
A1 Huang, Ling-jie
A1 Li, Yi-ning
A1 Wu, Ting-ting
A1 Zhong, Jiang-yan
A1 Cao, Qian
A1 Li, Yi-yuan
A1 Jin, Jin
YR 2021
UL http://advances.sciencemag.org/content/7/3/eabc4009.abstract
AB 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 Nfkb1-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.