The Role of E3 Ubiquitin Ligases and Deubiquitinases in Inflammatory Bowel Disease: Friend or Foe?

Abstract

Inflammatory bowel disease (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), exhibits a complex multifactorial pathogenesis involving genetic susceptibility, imbalance of gut microbiota, mucosal immune disorder and environmental factors. Recent studies reported associations between ubiquitination and deubiquitination and the occurrence and development of inflammatory bowel disease. Ubiquitination modification, one of the most important types of post-translational modifications, is a multi-step enzymatic process involved in the regulation of various physiological processes of cells, including cell cycle progression, cell differentiation, apoptosis, and innate and adaptive immune responses. Alterations in ubiquitination and deubiquitination can lead to various diseases, including IBD. Here, we review the role of E3 ubiquitin ligases and deubiquitinases (DUBs) and their mediated ubiquitination and deubiquitination modifications in the pathogenesis of IBD. We highlight the importance of this type of posttranslational modification in the development of inflammation, and provide guidance for the future development of targeted therapeutics in IBD.

Roles of ubiquitin-specific proteases in inflammatory diseases

“…Nonetheless, due to the high homology among members of the USP family, achieving specificity with USP inhibitors poses a significant challenge ( 164 ). This results in the existing inhibitors lacking specificity and often failing to exclusively target a single member of USPs, thereby somewhat limiting their utility.…”

“…This results in the existing inhibitors lacking specificity and often failing to exclusively target a single member of USPs, thereby somewhat limiting their utility. For instance, drugs like PR619 target a range of enzymes including USP2, USP4, USP5, USP7, USP8, USP15, USP20, USP28, USP47, UCHL1, UCHL3, UCHL5, highlighting the need to craft more selective agents ( 164 ). A prime example is the subsequent USP1 inhibitor ML323, exhibiting higher specificity compared to previous compounds like Pimozide and GW7647, thereby widening its scope of application ( 164 ).…”

“…For instance, drugs like PR619 target a range of enzymes including USP2, USP4, USP5, USP7, USP8, USP15, USP20, USP28, USP47, UCHL1, UCHL3, UCHL5, highlighting the need to craft more selective agents ( 164 ). A prime example is the subsequent USP1 inhibitor ML323, exhibiting higher specificity compared to previous compounds like Pimozide and GW7647, thereby widening its scope of application ( 164 ). To achieve enhanced specificity in inhibitors, careful consideration of the chemical structure of USPs is needed ( 164 ).…”

“…A prime example is the subsequent USP1 inhibitor ML323, exhibiting higher specificity compared to previous compounds like Pimozide and GW7647, thereby widening its scope of application ( 164 ). To achieve enhanced specificity in inhibitors, careful consideration of the chemical structure of USPs is needed ( 164 ). Nowadays, it is crucial to search for and apply suitable biological testing methods to screen and identify small molecule inhibitors of USPs.…”

Structural analysis shows that the BIR2 domain of E3 ligase XIAP binds across the RIP2 kinase dimer interface

“…IBDs, which include Crohn’s disease (CD) and ulcerative colitis (UC), are a major social health problem in need of novel treatments (Kaplan & Windsor, 2021). Loss of function by mutations of NOD2 or ATG16L1 and misregulation of ubiquitination/deubiquitination in the NOD pathway can result in a genetic susceptibility to develop IBDs (Zou et al, 2021; Ananthakrishnan AN, 2015; Cho & Abraham, 2007; Philpott et al, 2014; Caruso, R., Lo, B.C. & Núñez, 2020; Kuballa et al, 2008; Cooney et al, 2010; Honjo et al, 2021a; Sámano-Sánchez & Gibson, 2020; Inohara et al, 2003).…”