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

The classic NF-kappa B pathway plays crucial roles in various immune responses and inflammatory diseases. Its key kinase, IKK beta, participates in a variety of pathological and physiological processes by selectively recognizing its downstream substrates, including p105, p65, and I kappa B alpha, 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 IKK beta ubiquitination on lysine-238 was substantially increased during inflammation. Using mass spectrometry, we identified USP16 as an essential regulator of the IKK beta ubiquitination level that selectively affected p105 phosphorylation without directly affecting p65 or I kappa B alpha 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.

Automated summary

The classic NF-kappa B pathway is crucial in immune responses and inflammatory diseases. This study showed that IKK beta ubiquitination on lysine-238 increases during inflammation, with USP16 identified as a key regulator affecting p105 phosphorylation. Elevated expression of USP16 in colon macrophages of IBD patients and conditional knockout of USP16 in myeloid cells resulted in reduced severity of IBD, providing insights for targeted intervention therapy.