期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-09667-z
关键词
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资金
- Kom op tegen Kanker (Stand up to Cancer) grant from the Flemish cancer society
- FWO
- Geneeskundige Stichting Koningin Elisabeth (GSKE)
- CBC Banque Prize
- Charcot Foundation
- Belgian Foundation against Cancer
- Concerted Research Actions (GOA) of the Ghent University
- Fundacion Moraza (USAL)
- FPU (Spanish Government)
- Spanish Government [SAF2014-53320-R, SAF2017-88390-R]
- Broad Medical Research Program (Crohn's and Colitis Foundation, USA) [IBD-0369]
- Junta de Castilla y Leon local government [FIC016U14]
- [PRB3 (IPT17/0019-ISCIII-SGEFI/ERDF)]
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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