Ubiquitin ligase TRIM27 promotes a novel mechanism of intestinal stem cell self-renewal and maintenance of intestinal homeostasis

In the process of exploring the host immune regulation mechanism of Mycobacterium tuberculosis (Mtb), the team of Cuihua Liu of the Institute of Microbiology found that multiple pathogenic secretory effector proteins closely related to the survival of Mtb cells jointly targeted the host's ubiquitin ligase TRIM27 protein (Tripartite motif-containing 27), and further constructed the Trim27 gene knockout (Trim27-^/- The mouse was later found to have a phenotype of spontaneous enteritis, suggesting that the host protein TRIM27 targeted by Mtb may not only play a role in the host's anti-infection immunity, but also participate in the regulation of the body's intestinal inflammation immune homeostasis, and studies have also suggested that TRIM27 plays a regulatory role in the development of infection, inflammation and tumors, but its physiological function and exact regulatory mechanism are far from clear
.

The latest collaborative research between this research group and Wang Jing Research Group of the Institute of Microbiology and Zhang Lingqiang's research team of the Military Medical Research Institute of the Academy of Military Sciences revealed that the ubiquitin ligase TRIM27 is a key regulator
of intestinal homeostasis maintenance 。 First, by collecting intestinal tissue microarray data from patients with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), two common intestinal homeostasis disorders, and analyzing their gene expression, the team found that the gene expression levels of TRIM27 in patients with both types of diseases changed significantly.
It suggests that it is an important host genetic factor
for the maintenance of intestinal homeostasis.
Interestingly, TRIM27 is highly expressed in the intestinal tissue of IBD patients, but low in IBS patients, especially diarrhea predominant IBS (IBS-D), indicating that TRIM27 may play a precise regulatory role
in the maintenance of intestinal homeostasis.
The team members further constructed Trim27 whole gene knockout (Trim27-^/-) mice and found that mice lacking TRIM27 showed IBS-like symptoms such as increased visceral hypersensitivity, increased number of defecal particles, low-grade inflammation of the intestinal mucosa, damage to the intestinal barrier, and dysbacteriosis of intestinal flora, and these symptoms gradually intensified
with the increase of the age of the mice 。 Subsequent mechanism exploration experiments showed that TRIM27 was mainly localized in mouse intestinal stem cells (ISCs), competitively bound to the ARM (Armadillo) domain of β-catenin in a CC (coiled-coil) domain-dependent and ubiquitin-linkase activity independent manner, thereby inhibiting GSK-3β- The phosphorylation modification of β-catenin mediated by the CK1-Axin complex and the subsequent ubiquitination modification and proteasome degradation improved the stability of β-catenin protein, promoted the activation of Wnt/β-catenin signaling pathway, and ultimately promoted the self-renewal
of ISCs.
This mechanism has also been validated
in mice with intestinal stem cell-specific knockout of Trim27 (trim27 [Lgr5]).
In addition, the treatment of trim27 [Lgr5] mice with the Wnt/β-catenin signaling pathway activator SKL2001 and probiotic preparations effectively restored the self-renewal ability of ISCs, thereby alleviating IBS-like symptoms in trim27 [Lgr5] mice (Figure 1).

In this study, the key genetic protection factor of IBS, TRIM27, was identified and its mechanism of action was elucidated, and the Trim27 knockout mouse model constructed in this study could be used as a mouse model for spontaneous IBS, which could provide an important tool
for subsequent IBS pathogenesis exploration and development of prevention and control methods.
The regulatory role and molecular mechanism
of intestinal stem cell homeostasis and its mediated intestinal epithelial barrier integrity in IBS were revealed.
A new strategy for IBS targeting the TRIM27/Wnt/β-catenin signaling axis was proposed, suggesting that TRIM27 is a potential biomarker
to distinguish IBS and IBD from two chronic intestinal inflammatory diseases with similar symptoms.

The findings have been published online in Cellular & Molecular Immunology under the title "TRIM27 maintains gut homeostasis by promoting intestinal stem cell self-renewal.
"
。 Professor Wang Jing of the Institute of Microbiology, Chinese Academy of Sciences, doctoral students Zhao Dongdong and Lei Zehui and postdoctoral fellow Ge Pupu of Liu Cuihua's research group are co-first authors of the paper, and researcher Liu Cuihua and researcher Zhang Lingqiang of the Institute of Military Medical Sciences and National Center for Protein Science (Beijing) of the Academy of Military Sciences are co-corresponding authors
of this paper.
The research was supported
by the National Key R&D Program, the National Natural Science Foundation of China, the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences (Class B), the Independent Project Fund of the State Key Laboratory of Proteomics, and the Talent Program of the Youth Innovation Promotion Association of the Chinese Academy of Sciences.

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