Physical and functional interaction between A20 and ATG16L1-WD40 domain in the control of intestinal homeostasis

Karolina Slowicka, Inmaculada Serramito-Gómez, Emilio Boada-Romero, Arne Martens, Mozes Sze, Ioanna Petta, Hanna K. Vikkula, Riet De Rycke, Eef Parthoens, Saskia Lippens, Savvas N. Savvides, Andy Wullaert, Lars Vereecke, Felipe X. Pimentel-Muiños () and Geert van Loo ()
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Karolina Slowicka: VIB Center for Inflammation Research
Inmaculada Serramito-Gómez: CSIC-Universidad de Salamanca
Emilio Boada-Romero: CSIC-Universidad de Salamanca
Arne Martens: VIB Center for Inflammation Research
Mozes Sze: VIB Center for Inflammation Research
Ioanna Petta: VIB Center for Inflammation Research
Hanna K. Vikkula: VIB Center for Inflammation Research
Riet De Rycke: VIB Center for Inflammation Research
Eef Parthoens: VIB Center for Inflammation Research
Saskia Lippens: VIB Center for Inflammation Research
Savvas N. Savvides: VIB Center for Inflammation Research
Andy Wullaert: VIB Center for Inflammation Research
Lars Vereecke: VIB Center for Inflammation Research
Felipe X. Pimentel-Muiños: CSIC-Universidad de Salamanca
Geert van Loo: VIB Center for Inflammation Research

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09667-z

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