Research ArticleIMMUNOLOGY

Substrate-specific recognition of IKKs mediated by USP16 facilitates autoimmune inflammation

See allHide authors and affiliations

Science Advances  13 Jan 2021:
Vol. 7, no. 3, eabc4009
DOI: 10.1126/sciadv.abc4009


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.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

View Full Text

Stay Connected to Science Advances