Two distinct ubiquitin-binding motifs in A20 mediate its anti-inflammatory and cell-protective activities.

Nature immunology 2020 Apr

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Protein ubiquitination regulates protein stability and modulates the composition of signaling complexes. A20 is a negative regulator of inflammatory signaling, but the molecular mechanisms involved are ill understood. Here, we generated Tnfaip3 gene-targeted A20 mutant mice bearing inactivating mutations in the zinc finger 7 (ZnF7) and ZnF4 ubiquitin-binding domains, revealing that binding to polyubiquitin is essential for A20 to suppress inflammatory disease. We demonstrate that a functional ZnF7 domain was required for recruiting A20 to the tumor necrosis factor receptor 1 (TNFR1) signaling complex and to suppress inflammatory signaling and cell death. The combined inactivation of ZnF4 and ZnF7 phenocopied the postnatal lethality and severe multiorgan inflammation of A20-deficient mice. Conditional tissue-specific expression of mutant A20 further revealed the key role of ubiquitin-binding in myeloid and intestinal epithelial cells. Collectively, these results demonstrate that the anti-inflammatory and cytoprotective functions of A20 are largely dependent on its ubiquitin-binding properties.

Citation

Arne Martens, Dario Priem, Esther Hoste, Jessica Vetters, Sofie Rennen, Leen Catrysse, Sofie Voet, Laura Deelen, Mozes Sze, Hanna Vikkula, Karolina Slowicka, Tino Hochepied, Kalliopi Iliaki, Andy Wullaert, Sophie Janssens, Mohamed Lamkanfi, Rudi Beyaert, Marietta Armaka, Mathieu J M Bertrand, Geert van Loo. Two distinct ubiquitin-binding motifs in A20 mediate its anti-inflammatory and cell-protective activities. Nature immunology. 2020 Apr;21(4):381-387