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

作者：Jiangyun Shen, Liyan Lou, Xue Du, Bincheng Zhou, Yanqi Xu, Fuqi Mei, Liangrong Wu, Jianmin Li, Ari Waisman, Jing Ruan, Xu Wang · 发表于：EMBO Reports · 年份：2024 · DOI：10.1038/s44319-024-00276-6 · 被引用次数：10 · 研究领域：Ubiquitin and proteasome pathways、Immune cells in cancer、Immunotherapy and Immune Responses

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.