The deubiquitinase OTUD1 inhibits colonic inflammation by suppressing RIPK1-mediated NF-κB signaling

Wu, Bo; Qiang, Lihua; Zhang, Yong; Fu, Yesheng; Zhao, Mengyuan; Lei, Zehui; Lü, Zhe; Wei, Yange; Dai, Hongmiao; Ge, Yingwei; Liu, Mingqiu; Zhou, Xuemei; Peng, Zhiqiang; Li, Hongchang; Chu, Chun-Ping; Wang, Jing; Zheng, Hui; Liu, Cui Hua; Zhang, Lingqiang

doi:10.1038/s41423-021-00810-9

Cited by 55 publications

(27 citation statements)

References 42 publications

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“… 24–27 Among them, the DSS model has become the preferred modeling method to study UC in China and abroad due to pathological and clinical manifestations that are very similar to human UC. 28–32 …”

Section: Introductionmentioning

confidence: 99%

Dynamic Changes in Gut Microbiome of Ulcerative Colitis: Initial Study from Animal Model

Gu¹,

Zhang²,

Han³

et al. 2022

JIR

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Background An animal model of DSS-induced UC has been widely used in basic research, and the dysbiosis of gut microbiome is one of the important pathogenetic mechanisms of DSS-induced UC, but its dynamic changes and correlation with inflammatory factors are not clear yet. Methods Clinical signs and tissue damage degree of C57BL/6 ulcerative colitis mice model induced by different concentrations of DSS were compared with that of normal mice, and finally the optimal concentration of DSS was determined. Then we analyzed the sequencing results of gut microbiome and inflammatory factors to determine the dynamic patterns of gut microbiome and their correlation with the inflammatory factors. Results DSS at 2.5% and 3.0% concentration could cause intestinal injury and induce colitis. However, 3.0% DSS resulted in higher mortality. In addition, there were dynamic changes of gut microbiome in DSS-induced UC model: the relative abundance of intestinal flora increased first and then decreased in Bacteroides , Parabacteroides , Romboutsia , Clostridium_sensu_stricto_1, Lachnospiraceae_NK4A136_group, norank_f_norank_o_Clostridia_UCG-014, Parasutterella , and decreased first and then increased in Lactobacillus , Muribaculum , norank_f_Muribaculaceae, in addition, Bifidobacterium , Coriobacteriaceae_UCG-002 and Enterorhabdus did not change in the first 14 days but increased significantly on day 21. Moreover, inflammatory cytokines were closely associated with the imbalance of the intestinal microbiota in mice with UC: most pathogenic bacteria in the intestinal tract of the UC animal model were positively correlated with pro-inflammatory factors and negatively correlated with anti-inflammatory factors, while beneficial bacteria were the opposite. Conclusion Intestinal microecology plays an important role in DSS-induced UC model, and the relative abundance of gut microbiome changes dynamically in the occurrence and development of ulcerative colitis.

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Section: Introductionmentioning

confidence: 99%

Dynamic Changes in Gut Microbiome of Ulcerative Colitis: Initial Study from Animal Model

Gu¹,

Zhang²,

Han³

et al. 2022

JIR

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“…A recent report showed that OTUD1 inhibits colonic inflammation in vivo [ 28 ]. We confirmed that significant shortening of the colon, and higher diarrhea and fecal blood scores were observed in a DSS-administrated ulcerative colitis-like inflammatory bowel disease (IBD) model of Otud1 −/− -mice (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…OTUD1 reportedly regulates the Hippo pathway [ 37 ]. Furthermore, quite recently OTUD1 was found to suppress IBD by removing the K63 ubiquitin chain from RIP1 [ 28 ]. Collectively, these findings indicate that OTUD1 functions as a crucial regulator of cancer progression, antiviral host defense responses, and inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

OTUD1 deubiquitinase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways

Oikawa¹,

Kosako

et al. 2022

Cell Death Dis

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Deubiquitinating enzymes (DUBs) regulate numerous cellular functions by removing ubiquitin modifications. We examined the effects of 88 human DUBs on linear ubiquitin chain assembly complex (LUBAC)-induced NF-κB activation, and identified OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-κB pathway by hydrolyzing K63-linked ubiquitin chains from NF-κB signaling factors, including LUBAC. OTUD1 negatively regulates the canonical NF-κB activation, apoptosis, and necroptosis, whereas OTUD1 upregulates the interferon (IFN) antiviral pathway. Mass spectrometric analysis showed that OTUD1 binds KEAP1, and the N-terminal intrinsically disordered region of OTUD1, which contains an ETGE motif, is indispensable for the KEAP1-binding. Indeed, OTUD1 is involved in the KEAP1-mediated antioxidant response and reactive oxygen species (ROS)-induced cell death, oxeiptosis. In Otud1−/−-mice, inflammation, oxidative damage, and cell death were enhanced in inflammatory bowel disease, acute hepatitis, and sepsis models. Thus, OTUD1 is a crucial regulator for the inflammatory, innate immune, and oxidative stress responses and ROS-associated cell death pathways.

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“…Thus, it would be very interesting to explore whether and how resveratrol shapes intestinal barrier via lncRNAs. In addition, a novel experiment has been well demonstrated that the ovarian tumor deubiquitinase 1 (OTUD1) alleviates IBD through inhibiting receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-mediated NF-κB activation ( 139 ). Therefore, whether and how resveratrol interacts with OTUD1 to mediate intestinal barrier and ultimately regulate IBD should also be taken into consideration.…”

Section: Prospects For Futurementioning

confidence: 99%

Resveratrol in Intestinal Health and Disease: Focusing on Intestinal Barrier

Wang

Hong

et al. 2022

Front. Nutr.

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The integrity of intestinal barrier determines intestinal homeostasis, which could be affected by various factors, like physical, chemical, and biological stimuli. Therefore, it is of considerable interest and importance to maintain intestinal barrier function. Fortunately, many plant polyphenols, including resveratrol, could affect the health of intestinal barrier. Resveratrol has many biological functions, such as antioxidant, anti-inflammation, anti-tumor, and anti-cardiovascular diseases. Accumulating studies have shown that resveratrol affects intestinal tight junction, microbial composition, and inflammation. In this review, we summarize the effects of resveratrol on intestinal barriers as well as the potential mechanisms (e.g., inhibiting the growth of pathogenic bacteria and fungi, regulating the expression of tight junction proteins, and increasing anti-inflammatory T cells while reducing pro-inflammatory T cells), and highlight the applications of resveratrol in ameliorating various intestinal diseases.

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The deubiquitinase OTUD1 inhibits colonic inflammation by suppressing RIPK1-mediated NF-κB signaling

Cited by 55 publications

References 42 publications

Dynamic Changes in Gut Microbiome of Ulcerative Colitis: Initial Study from Animal Model

Dynamic Changes in Gut Microbiome of Ulcerative Colitis: Initial Study from Animal Model

OTUD1 deubiquitinase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways

Resveratrol in Intestinal Health and Disease: Focusing on Intestinal Barrier

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