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The deubiquitinase OTUD4 inhibits the expression of antimicrobial peptides in Paneth cells to support intestinal inflammation and bacterial infection
Dysfunction of the intestinal epithelial barrier causes microbial invasion that would lead to inflammation in the gut. Antimicrobial peptides (AMPs) are essential components of the intestinal epithelial barrier, while the regulatory mechanisms of AMPs expression are not fully characterized. Here, we...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10123543/ https://www.ncbi.nlm.nih.gov/pubmed/37193092 http://dx.doi.org/10.1016/j.cellin.2023.100100 |
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author | Yu, Keying Guo, Yu-Yao Liuyu, Tianzi Wang, Peng Zhang, Zhi-Dong Lin, Dandan Zhong, Bo |
author_facet | Yu, Keying Guo, Yu-Yao Liuyu, Tianzi Wang, Peng Zhang, Zhi-Dong Lin, Dandan Zhong, Bo |
author_sort | Yu, Keying |
collection | PubMed |
description | Dysfunction of the intestinal epithelial barrier causes microbial invasion that would lead to inflammation in the gut. Antimicrobial peptides (AMPs) are essential components of the intestinal epithelial barrier, while the regulatory mechanisms of AMPs expression are not fully characterized. Here, we report that the ovarian tumor family deubiquitinase 4 (OTUD4) in Paneth cells restricts the expression of AMPs and thereby promotes experimental colitis and bacterial infection. OTUD4 is upregulated in the inflamed mucosa of ulcerative colitis patients and in the colon of mice treated with dextran sulfate sodium salt (DSS). Knockout of OTUD4 promotes the expression of AMPs in intestinal organoids after stimulation with lipopolysaccharide (LPS) or peptidoglycan (PGN) and in the intestinal epithelial cells (IECs) of mice after DSS treatment or Salmonella typhimurium (S.t.) infection. Consistently, Vil-Cre;Otud4(fl/fl) mice and Def-Cre;Otud4(fl/fl) mice exhibit hyper-resistance to DSS-induced colitis and S.t. infection compared to Otud4(fl/fl) mice. Mechanistically, knockout of OTUD4 results in hyper K63-linked ubiquitination of MyD88 and increases the activation of NF-κB and MAPKs to promote the expression of AMPs. These findings collectively highlight an indispensable role of OTUD4 in Paneth cells to modulate AMPs production and indicate OTUD4 as a potential target for gastrointestinal inflammation and bacterial infection. |
format | Online Article Text |
id | pubmed-10123543 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-101235432023-05-15 The deubiquitinase OTUD4 inhibits the expression of antimicrobial peptides in Paneth cells to support intestinal inflammation and bacterial infection Yu, Keying Guo, Yu-Yao Liuyu, Tianzi Wang, Peng Zhang, Zhi-Dong Lin, Dandan Zhong, Bo Cell Insight Research Article Dysfunction of the intestinal epithelial barrier causes microbial invasion that would lead to inflammation in the gut. Antimicrobial peptides (AMPs) are essential components of the intestinal epithelial barrier, while the regulatory mechanisms of AMPs expression are not fully characterized. Here, we report that the ovarian tumor family deubiquitinase 4 (OTUD4) in Paneth cells restricts the expression of AMPs and thereby promotes experimental colitis and bacterial infection. OTUD4 is upregulated in the inflamed mucosa of ulcerative colitis patients and in the colon of mice treated with dextran sulfate sodium salt (DSS). Knockout of OTUD4 promotes the expression of AMPs in intestinal organoids after stimulation with lipopolysaccharide (LPS) or peptidoglycan (PGN) and in the intestinal epithelial cells (IECs) of mice after DSS treatment or Salmonella typhimurium (S.t.) infection. Consistently, Vil-Cre;Otud4(fl/fl) mice and Def-Cre;Otud4(fl/fl) mice exhibit hyper-resistance to DSS-induced colitis and S.t. infection compared to Otud4(fl/fl) mice. Mechanistically, knockout of OTUD4 results in hyper K63-linked ubiquitination of MyD88 and increases the activation of NF-κB and MAPKs to promote the expression of AMPs. These findings collectively highlight an indispensable role of OTUD4 in Paneth cells to modulate AMPs production and indicate OTUD4 as a potential target for gastrointestinal inflammation and bacterial infection. Elsevier 2023-04-05 /pmc/articles/PMC10123543/ /pubmed/37193092 http://dx.doi.org/10.1016/j.cellin.2023.100100 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Yu, Keying Guo, Yu-Yao Liuyu, Tianzi Wang, Peng Zhang, Zhi-Dong Lin, Dandan Zhong, Bo The deubiquitinase OTUD4 inhibits the expression of antimicrobial peptides in Paneth cells to support intestinal inflammation and bacterial infection |
title | The deubiquitinase OTUD4 inhibits the expression of antimicrobial peptides in Paneth cells to support intestinal inflammation and bacterial infection |
title_full | The deubiquitinase OTUD4 inhibits the expression of antimicrobial peptides in Paneth cells to support intestinal inflammation and bacterial infection |
title_fullStr | The deubiquitinase OTUD4 inhibits the expression of antimicrobial peptides in Paneth cells to support intestinal inflammation and bacterial infection |
title_full_unstemmed | The deubiquitinase OTUD4 inhibits the expression of antimicrobial peptides in Paneth cells to support intestinal inflammation and bacterial infection |
title_short | The deubiquitinase OTUD4 inhibits the expression of antimicrobial peptides in Paneth cells to support intestinal inflammation and bacterial infection |
title_sort | deubiquitinase otud4 inhibits the expression of antimicrobial peptides in paneth cells to support intestinal inflammation and bacterial infection |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10123543/ https://www.ncbi.nlm.nih.gov/pubmed/37193092 http://dx.doi.org/10.1016/j.cellin.2023.100100 |
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