Article ; Online: Physical and functional interaction between A20 and ATG16L1-WD40 domain in the control of intestinal homeostasis.
2019 Volume 10, Issue 1, Page(s) 1834
Abstract: Prevention of inflammatory bowel disease (IBD) relies on tight control of inflammatory, cell death and autophagic mechanisms, but how these pathways are integrated at the molecular level is still unclear. Here we show that the anti-inflammatory protein ... ...
| Abstract | Prevention of inflammatory bowel disease (IBD) relies on tight control of inflammatory, cell death and autophagic mechanisms, but how these pathways are integrated at the molecular level is still unclear. Here we show that the anti-inflammatory protein A20 and the critical autophagic mediator Atg16l1 physically interact and synergize to regulate the stability of the intestinal epithelial barrier. A proteomic screen using the WD40 domain of ATG16L1 (WDD) identified A20 as a WDD-interacting protein. Loss of A20 and Atg16l1 in mouse intestinal epithelium induces spontaneous IBD-like pathology, as characterized by severe inflammation and increased intestinal epithelial cell death in both small and large intestine. Mechanistically, absence of A20 promotes Atg16l1 accumulation, while elimination of Atg16l1 or expression of WDD-deficient Atg16l1 stabilizes A20. Collectively our data show that A20 and Atg16l1 cooperatively control intestinal homeostasis by acting at the intersection of inflammatory, autophagy and cell death pathways. |
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| MeSH term(s) | Animals ; Autophagy/immunology ; Autophagy-Related Proteins ; Carrier Proteins/genetics ; Carrier Proteins/immunology ; Carrier Proteins/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Endoscopy ; Female ; Homeostasis/immunology ; Humans ; Inflammatory Bowel Diseases/diagnostic imaging ; Inflammatory Bowel Diseases/genetics ; Inflammatory Bowel Diseases/immunology ; Inflammatory Bowel Diseases/pathology ; Intestinal Mucosa/cytology ; Intestinal Mucosa/diagnostic imaging ; Intestinal Mucosa/immunology ; Intestinal Mucosa/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Protein Binding/immunology ; Proteomics ; Tumor Necrosis Factor alpha-Induced Protein 3/genetics ; Tumor Necrosis Factor alpha-Induced Protein 3/immunology ; Tumor Necrosis Factor alpha-Induced Protein 3/metabolism ; WD40 Repeats/genetics ; WD40 Repeats/immunology |
| Chemical Substances | Atg16l1 protein, mouse ; Autophagy-Related Proteins ; Carrier Proteins ; Tumor Necrosis Factor alpha-Induced Protein 3 (EC 3.4.19.12) ; Tnfaip3 protein, mouse (EC 3.4.22.-) |
| Language | English |
| Publishing date | 2019-04-23 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2553671-0 |
| ISSN | 2041-1723 ; 2041-1723 |
| ISSN (online) | 2041-1723 |
| ISSN | 2041-1723 |
| DOI | 10.1038/s41467-019-09667-z |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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