YOD1 sustains NOD2-mediated protective signaling in colitis by stabilizing RIPK2.

EMBO Rep

Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China.

Published: November 2024

Inflammatory bowel disease (IBD) is a disorder causing chronic inflammation in the gastrointestinal tract, and its pathophysiological mechanisms are still under investigation. Here, we find that mice deficient of YOD1, a deubiquitinating enzyme, are highly susceptible to dextran sulfate sodium (DSS)-induced colitis. The bone marrow transplantation experiment reveals that YOD1 derived from hematopoietic cells inhibits DSS colitis. Moreover, YOD1 exerts its protective role by promoting nucleotide-binding oligomerization domain 2 (NOD2)-mediated physiological inflammation in macrophages. Mechanistically, YOD1 inhibits the proteasomal degradation of receptor-interacting serine/threonine kinase 2 (RIPK2) by reducing its K48 polyubiquitination, thereby increasing RIPK2 abundance to enhance NOD2 signaling. Consistently, the protective function of muramyldipeptide, a NOD2 ligand, in experimental colitis is abolished in mice deficient of YOD1. Importantly, YOD1 is upregulated in colon-infiltrating macrophages in patients with colitis. Collectively, this study identifies YOD1 as a novel regulator of colitis.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549337PMC
http://dx.doi.org/10.1038/s44319-024-00276-6DOI Listing

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