2. Academic Validation
  3. YOD1 sustains NOD2-mediated protective signaling in colitis by stabilizing RIPK2

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

  • EMBO Rep. 2024 Nov;25(11):4827-4845. doi: 10.1038/s44319-024-00276-6.
Jiangyun Shen 1,  Liyan Lou 1,  Xue Du 1,  Bincheng Zhou 1,  Yanqi Xu 1,  Fuqi Mei 1,  Liangrong Wu 1 2,  Jianmin Li 3,  Ari Waisman 4,  Jing Ruan 5,  Xu Wang 6
Affiliations

Affiliations

  • 1 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China.
  • 2 Department of Pharmacy, Yiwu Central Hospital, 322099, Yiwu, China.
  • 3 Department of Pathology, The First Affiliated Hospital, Wenzhou Medical University, 325000, Wenzhou, China.
  • 4 Institute for Molecular Medicine, Johannes Gutenberg University Mainz, 55131, Mainz, Germany.
  • 5 Department of Pathology, The First Affiliated Hospital, Wenzhou Medical University, 325000, Wenzhou, China. ruanjing850617@163.com.
  • 6 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China. sunrim@163.com.
PMID: 39333628 DOI: 10.1038/s44319-024-00276-6
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.

Keywords

Inflammatory Bowel Disease; NOD2; RIPK2; Ubiquitination; YOD1.

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