1. YOD1 sustains NOD2-mediated protective signaling in colitis by stabilizing RIPK2.
- Author
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Shen, Jiangyun, Lou, Liyan, Du, Xue, Zhou, Bincheng, Xu, Yanqi, Mei, Fuqi, Wu, Liangrong, Li, Jianmin, Waisman, Ari, Ruan, Jing, and Wang, Xu
- Abstract
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. Synopsis: NOD2-mediated physiological inflammation is critical for maintaining intestinal homeostasis. The deubiquitinating enzyme YOD1 potentiates protective NOD2 signaling by stabilizing RIPK2, thereby ameliorating intestinal inflammation and colitis. Deficiency of YOD1 in hematopoietic cells exacerbates DSS-induced experimental colitis in mice. YOD1 is highly expressed in mucosa-infiltrating macrophages and potentiates inflammatory responses in macrophages. YOD1 enhances NOD2 signaling by stabilizing RIPK2 through K48 deubiquitylation. NOD2-mediated physiological inflammation is critical for maintaining intestinal homeostasis. The deubiquitinating enzyme YOD1 potentiates protective NOD2 signaling by stabilizing RIPK2, thereby ameliorating intestinal inflammation and colitis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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