OTULIN protects the intestinal epithelium from apoptosis during inflammation and infection
Abstract The intestinal epithelium is a single cell layer that is constantly renewed and acts as a physical barrier that separates intestinal microbiota from underlying tissues. In inflammatory bowel disease (IBD) in humans, as well as in experimental mouse models of IBD, this barrier is impaired, c...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06058-7 |
| _version_ | 1797740729500434432 |
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| author | Lien Verboom Christopher J. Anderson Maude Jans Ioanna Petta Gillian Blancke Arne Martens Mozes Sze Tino Hochepied Kodi S. Ravichandran Lars Vereecke Geert van Loo |
| author_facet | Lien Verboom Christopher J. Anderson Maude Jans Ioanna Petta Gillian Blancke Arne Martens Mozes Sze Tino Hochepied Kodi S. Ravichandran Lars Vereecke Geert van Loo |
| author_sort | Lien Verboom |
| collection | DOAJ |
| description | Abstract The intestinal epithelium is a single cell layer that is constantly renewed and acts as a physical barrier that separates intestinal microbiota from underlying tissues. In inflammatory bowel disease (IBD) in humans, as well as in experimental mouse models of IBD, this barrier is impaired, causing microbial infiltration and inflammation. Deficiency in OTU deubiquitinase with linear linkage specificity (OTULIN) causes OTULIN-related autoinflammatory syndrome (ORAS), a severe inflammatory pathology affecting multiple organs including the intestine. We show that mice with intestinal epithelial cell (IEC)-specific OTULIN deficiency exhibit increased susceptibility to experimental colitis and are highly sensitive to TNF toxicity, due to excessive apoptosis of OTULIN deficient IECs. OTULIN deficiency also increases intestinal pathology in mice genetically engineered to secrete excess TNF, confirming that chronic exposure to TNF promotes epithelial cell death and inflammation in OTULIN deficient mice. Mechanistically we demonstrate that upon TNF stimulation, OTULIN deficiency impairs TNF receptor complex I formation and LUBAC recruitment, and promotes the formation of the cytosolic complex II inducing epithelial cell death. Finally, we show that OTULIN deficiency in IECs increases susceptibility to Salmonella infection, further confirming the importance of OTULIN for intestinal barrier integrity. Together, these results identify OTULIN as a major anti-apoptotic protein in the intestinal epithelium and provide mechanistic insights into how OTULIN deficiency drives gastrointestinal inflammation in ORAS patients. |
| first_indexed | 2024-03-12T14:16:36Z |
| format | Article |
| id | doaj.art-7eadb0df90114b9c9cc7180ab08eeb46 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-12T14:16:36Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-7eadb0df90114b9c9cc7180ab08eeb462023-08-20T11:22:29ZengNature Publishing GroupCell Death and Disease2041-48892023-08-0114811310.1038/s41419-023-06058-7OTULIN protects the intestinal epithelium from apoptosis during inflammation and infectionLien Verboom0Christopher J. Anderson1Maude Jans2Ioanna Petta3Gillian Blancke4Arne Martens5Mozes Sze6Tino Hochepied7Kodi S. Ravichandran8Lars Vereecke9Geert van Loo10VIB Center for Inflammation ResearchVIB Center for Inflammation ResearchVIB Center for Inflammation ResearchVIB Center for Inflammation ResearchVIB Center for Inflammation ResearchVIB Center for Inflammation ResearchVIB Center for Inflammation ResearchVIB Center for Inflammation ResearchVIB Center for Inflammation ResearchVIB Center for Inflammation ResearchVIB Center for Inflammation ResearchAbstract The intestinal epithelium is a single cell layer that is constantly renewed and acts as a physical barrier that separates intestinal microbiota from underlying tissues. In inflammatory bowel disease (IBD) in humans, as well as in experimental mouse models of IBD, this barrier is impaired, causing microbial infiltration and inflammation. Deficiency in OTU deubiquitinase with linear linkage specificity (OTULIN) causes OTULIN-related autoinflammatory syndrome (ORAS), a severe inflammatory pathology affecting multiple organs including the intestine. We show that mice with intestinal epithelial cell (IEC)-specific OTULIN deficiency exhibit increased susceptibility to experimental colitis and are highly sensitive to TNF toxicity, due to excessive apoptosis of OTULIN deficient IECs. OTULIN deficiency also increases intestinal pathology in mice genetically engineered to secrete excess TNF, confirming that chronic exposure to TNF promotes epithelial cell death and inflammation in OTULIN deficient mice. Mechanistically we demonstrate that upon TNF stimulation, OTULIN deficiency impairs TNF receptor complex I formation and LUBAC recruitment, and promotes the formation of the cytosolic complex II inducing epithelial cell death. Finally, we show that OTULIN deficiency in IECs increases susceptibility to Salmonella infection, further confirming the importance of OTULIN for intestinal barrier integrity. Together, these results identify OTULIN as a major anti-apoptotic protein in the intestinal epithelium and provide mechanistic insights into how OTULIN deficiency drives gastrointestinal inflammation in ORAS patients.https://doi.org/10.1038/s41419-023-06058-7 |
| spellingShingle | Lien Verboom Christopher J. Anderson Maude Jans Ioanna Petta Gillian Blancke Arne Martens Mozes Sze Tino Hochepied Kodi S. Ravichandran Lars Vereecke Geert van Loo OTULIN protects the intestinal epithelium from apoptosis during inflammation and infection Cell Death and Disease |
| title | OTULIN protects the intestinal epithelium from apoptosis during inflammation and infection |
| title_full | OTULIN protects the intestinal epithelium from apoptosis during inflammation and infection |
| title_fullStr | OTULIN protects the intestinal epithelium from apoptosis during inflammation and infection |
| title_full_unstemmed | OTULIN protects the intestinal epithelium from apoptosis during inflammation and infection |
| title_short | OTULIN protects the intestinal epithelium from apoptosis during inflammation and infection |
| title_sort | otulin protects the intestinal epithelium from apoptosis during inflammation and infection |
| url | https://doi.org/10.1038/s41419-023-06058-7 |
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