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YOD1 通过稳定 RIPK2 来维持 NOD2 介导的结肠炎保护性信号。

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

机构信息

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

Department of Pharmacy, Yiwu Central Hospital, 322099, Yiwu, China.

出版信息

EMBO Rep. 2024 Nov;25(11):4827-4845. doi: 10.1038/s44319-024-00276-6. Epub 2024 Sep 27.

DOI:10.1038/s44319-024-00276-6
PMID:39333628
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11549337/
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.

摘要

炎症性肠病（IBD）是一种导致胃肠道慢性炎症的疾病，其病理生理机制仍在研究中。在这里，我们发现缺乏去泛素化酶 YOD1 的小鼠对葡聚糖硫酸钠（DSS）诱导的结肠炎高度敏感。骨髓移植实验表明，源自造血细胞的 YOD1 抑制 DSS 结肠炎。此外，YOD1 通过促进巨噬细胞中核苷酸结合寡聚化结构域 2（NOD2）介导的生理性炎症发挥其保护作用。在机制上，YOD1 通过减少其 K48 多泛素化来抑制蛋白酶体降解受体相互作用丝氨酸/苏氨酸激酶 2（RIPK2），从而增加 RIPK2 的丰度以增强 NOD2 信号。一致地，NOD2 配体 muramyldipeptide 在缺乏 YOD1 的小鼠中对实验性结肠炎的保护作用被消除。重要的是，YOD1 在结肠炎患者的结肠浸润巨噬细胞中上调。总之，这项研究确定 YOD1 是结肠炎的一种新型调节剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/fda5fda89845/44319_2024_276_Fig9_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/c1e9ced475a5/44319_2024_276_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/4baca862809e/44319_2024_276_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/edd2adfdbb62/44319_2024_276_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/6392c0c00ff1/44319_2024_276_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/fda5fda89845/44319_2024_276_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/02604c39e650/44319_2024_276_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/dd28f7086250/44319_2024_276_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/81393f50503b/44319_2024_276_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/fc60dd89dab6/44319_2024_276_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/c1e9ced475a5/44319_2024_276_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/4baca862809e/44319_2024_276_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/edd2adfdbb62/44319_2024_276_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/6392c0c00ff1/44319_2024_276_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/537d/11549337/fda5fda89845/44319_2024_276_Fig9_ESM.jpg

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