ASB3 expression aggravates inflammatory bowel disease by targeting TRAF6 protein stability and affecting the intestinal microbiota

Author:

Cheng Mingyang1234ORCID,Xu Bin5,Sun Yu1234,Wang Junhong1234,Lu Yiyuan1234,Shi Chunwei1234,Pan Tianxu1234,Zhao Wenhui1234,Li Xiaoxu1234,Song Xiaomei6,Wang Jianzhong1234,Wang Nan1234,Yang Wentao1234,Jiang Yanlong1234,Huang Haibin1234,Yang Guilian1234,Zeng Yan1234ORCID,Yang Dongqin7ORCID,Wang Chunfeng1234ORCID,Cao Xin1234ORCID

Affiliation:

1. College of Veterinary Medicine, Jilin Agricultural University, Changchun, China

2. Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China

3. Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China

4. Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China

5. Department of General Surgery, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, China

6. Department of Gastroenterology, Chongqing General Hospital, Chongqing, China

7. Central Laboratory, Huashan Hospital, Fudan University, Shanghai, China

Abstract

ABSTRACT E3 ubiquitin ligase (E3) plays a vital role in regulating inflammatory responses by mediating ubiquitination. Previous studies have shown that ankyrin repeat and SOCS box-containing protein 3 (ASB3) is involved in immunomodulatory functions associated with cancer. However, the impact of ASB3 on the dynamic interplay of microbiota and inflammatory responses in inflammatory bowel disease (IBD) is unclear. Here, we systematically identify the E3 ligase ASB3 as a facilitative regulator in the development and progression of IBD. We observed that ASB3 exhibited significant upregulation in the lesions of patients with IBD. ASB3 −/− mice are resistant to dextran sodium sulfate-induced colitis. IκBα phosphorylation levels and production of proinflammatory factors IL-1β, IL-6, and TNF-α were reduced in the colonic tissues of ASB3 −/− mice compared to WT mice. This colitis-resistant phenotype was suppressed after coprophagic microbial transfer and reversed after combined antibiotics removed the gut commensal microbiome. Mechanistically, ASB3 specifically catalyzes K48-linked polyubiquitination of TRAF6 in intestinal epithelial cells. In contrast, in ASB3-deficient organoids, the integrity of the TRAF6 protein is shielded, consequently decelerating the onset of intestinal inflammation. ASB3 is associated with dysregulation of the colitis microbiota and promotes proinflammatory factors’ production by disrupting TRAF6 stability. Strategies to limit the protein level of ASB3 in intestinal epithelial cells may help in the treatment of colitis. IMPORTANCE Ubiquitination is a key process that controls protein stability. We determined the ubiquitination of TRAF6 by ASB3 in intestinal epithelial cells during colonic inflammation. Inflammatory bowel disease patients exhibit upregulated ASB3 expression at focal sites, supporting the involvement of degradation of TRAF6, which promotes TLR-Myd88/TRIF-independent NF-κB aberrant activation and intestinal microbiota imbalance. Sustained inflammatory signaling in intestinal epithelial cells and dysregulated protective probiotic immune responses mediated by ASB3 collectively contribute to the exacerbation of inflammatory bowel disease. These findings provide insights into the pathogenesis of inflammatory bowel disease and suggest a novel mechanism by which ASB3 increases the risk of colitis. Our results suggest that future inhibition of ASB3 in intestinal epithelial cells may be a novel clinical strategy.

Funder

MOST | National Natural Science Foundation of China

Science and Technology Development Program of Changchun city

China Agriculture Research System of MOF and MARA

MOST National Natural Science Foundation of China

Publisher

American Society for Microbiology

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