Research reveals a new mechanism for deubiquitinating enzyme OTUD1 to inhibit enteritis

Inflammatory bowel disease (IBD) is a type of recurrent chronic intestinal inflammatory disease caused by immune response disorders, including ulcerative colitis (UC) and Crohn's disease (CD), which mostly occur in the colon and terminal ileum
.

In recent decades, the incidence of IBD has shown a significant upward trend, and there is currently no clinically effective cure for IBD
.

The intestinal immune system can maintain intestinal immune homeostasis through a variety of cellular and molecular mechanisms, and its disorder may lead to a variety of inflammatory and immune diseases and even tumors
.

In-depth exploration of the regulation mechanism of the intestinal immune microenvironment homeostasis will provide new molecular markers for the prevention and treatment of intestinal immune diseases such as IBD
.

As an important deubiquitinating enzyme, OTUD1 can regulate autoimmune diseases, viral and fungal infections, and intestinal cancer, but its role in intestinal inflammatory diseases and its regulatory mechanism are still unclear
.

 Recently, Liu Cuihua’s team from the Institute of Microbiology, Chinese Academy of Sciences and Zhang Lingqiang’s team from the Academy of Military Medicine found that the deubiquitinating enzyme OTUD1 can bind to RIPK1 and remove its lysine 627 K63 polyubiquitination modification to prevent it.
RIPK1 recruits the downstream signaling molecule NEMO and activates the NF-κB signaling pathway, thereby inhibiting the production of pro-inflammatory cytokines (including TNF-α, IL-6 and IL-1β, etc.
) in the intestinal immune cells and the occurrence of enteritis
.

Studies have found that dextran sodium sulfate (DSS) treatment can induce an increase in the expression of OTUD1 in mouse colon tissues
.

The establishment of a DSS colitis model in Otud1 knockout mice found that Otud1 knockout promoted the production of pro-inflammatory cytokines and the occurrence of enteritis in the mouse intestinal tissue
.

At the same time, mouse bone marrow transplantation experiments also proved that OTUD1 expressed by myeloid cells is essential for the inhibitory effect of enteritis
.

Further mechanism exploration found that LPS can induce hypomethylation in the promoter region of OTUD1 to promote the high expression of OTUD1.
After that, OTUD1 interacts with RIPK1 and removes the K63 polyubiquitin chain of lysine 627 of RIPK1, thereby Inhibit its recruitment of NEMO and activation of NF-κB signaling pathway
.

The study also found that compared with healthy people, the expression of OTUD1 in the intestinal mucosa of UC patients was lower, and the OTUD1 G403V mutant associated with UC lost the ability to inhibit RIPK1-mediated NF-κB signal activation and enteritis
.

 The study revealed that the deubiquitinating enzyme OTUD1 inhibits the production of pro-inflammatory cytokines mediated by the NF-κB pathway in intestinal immune cells by removing the K63 polyubiquitin chain of RIPK1, thereby inhibiting the molecular mechanism of enteritis.
Immune intervention targeting the OTUD1-RIPK1 signal axis may be an effective way to treat IBD.
This study provides a new potential intervention target for the prevention and treatment of intestinal inflammatory diseases
.

 Related results were published on Cellular & Molecular Immunology
.

The research was funded by the National Biosafety Special Project, the National Natural Science Foundation of China, the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences, and the State Key Laboratory of Proteomics
.

 Schematic diagram of the mechanism by which deubiquitinating enzyme OTUD1 inhibits the occurrence of enteritis.
Source: Institute of Microbiology, Chinese Academy of Sciences