Fig. 1 Proposed model depicting TRIM27-maintained intestinal homeostasis by promoting ISC self-renewal

Dr. Liu Cuihua’s group, from the Institute of Microbiology of the Chinese Academy of Sciences (IMCAS), has been investigating the molecular mechanisms underlying pathogen infection and immune regulation. In recent years, Liu’s group has published a series of papers in journals such as Science, Nature Immunology, Nature Communications, Proc Natl Acad Sci, Autophagy, Cellular & Molecular Immunology, and EMBO reports. These studies reveal the underlying molecular mechanisms involved in pathogen infection and host immune regulation, providing new strategies and potential targets for the development of treatments against tuberculosis and related inflammatory diseases.

Recently, Dr. Liu Cuihua’s group, in collaboration with Dr. Wang Jing’s group from IMCAS as well as Dr. Zhang Lingqiang’s group from the National Center for Protein Sciences, Beijing, have revealed that TRIM27 (Tripartite motif containing 27), an E3 ligase of TRIM family proteins, is a critical genetic factor for maintaining intestinal homeostasis. Specifically, through analyzing the expression levels of TRIM family members in intestinal tissues of the two most common gastrointestinal disorders sharing overlapping symptoms, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), the E3 ubiquitin ligase TRIM27 was identified to be highly expressed in IBD patients while lowly expressed in IBS patients as compared with a healthy control group, suggesting that TRIM27 may play a delicate regulatory role in maintaining gut homeostasis. Furthermore, through establishing Trim27-knockout mouse models, they found that Trim27 deficiency induced IBS-like symptoms in mice, including low-grade intestinal mucosal inflammation, intestinal barrier impairment, visceral hypersensitivity, altered gastrointestinal motility and gut dysbiosis, which phenomenon gradually aggravates with increasing mouse age. Mechanistically, TRIM27 bounds to the conserved Armadillo (ARM) repeat of β-catenin in its Coiled-coil (CC) domain-dependent manner, independently of its E3 ubiquitin ligase activity, which proceeds the prevention of β-catenin from binding to Axin to inhibit the degradation of β-catenin, resulting in the activation of Wnt/β-catenin signaling to promote ISC self-renewal. Furthermore, Wnt/β-catenin signaling activator SKL2001 and probiotics treatment alleviates IBS-like symptoms in Trim27-knockout mice through promoting ISC self-renewal (Fig. 1).

The following highlights are the significant breakthroughs of this study: 1) This study reveals TRIM27 as a critical genetic protective factor for IBS. Importantly, Trim27-knockout mouse models established in this study spontaneously develop a series of symptoms similar to those of IBS-D patients, and could serve as a stable genetic-based tool for further mechanistic studies and drug development for IBS. 2) This study elucidates the regulatory mechanism of ISC homeostasis and its mediated intestinal epithelial barrier integrity in the pathogenesis of IBS. 3) This study provides a potential treatment for IBS via targeting the TRIM27/Wnt/β-catenin axis, and suggests that TRIM27 might serve as a biomarker for differentiating IBS from IBD.

The paper is entitled “TRIM27 maintains gut homeostasis by promoting intestinal stem cell self-renewal” and has been published online in Cellular & Molecular Immunology with Dr. Wang Jing, Zhao Dongdong, Lei Zehui and Ge Pupu as joint first authors, and Dr. Liu Cuihua and Dr. Zhang Lingqiang as joint corresponding authors.

For more information, please contact:

Dr. Liu Cuihua

E-mail: liucuihua@im.ac.cn

CAS Key Laboratory of Pathogenic Microbiology and Immunology,

Institute of Microbiology,

Chinese Academy of Sciences

Source: CAS Key Laboratory of Pathogenic Microbiology and Immunology,

Institute of Microbiology,

Chinese Academy of Sciences