Non-catalytic ubiquitin binding by A20 prevents psoriatic arthritis-like disease and inflammation

A20 is an anti-inflammatory protein that is strongly linked to human disease. Here we find that mice expressing three distinct targeted mutations of A20’s ZF7 ubiquitin binding motif uniformly developed digit arthritis that shares features with psoriatic arthritis, while mice expressing point mutations in A20’s OTU or ZF4 motifs did not exhibit this phenotype. Arthritis in A20(ZF7) mice required T cells and MyD88, was exquisitely sensitive to tumor necrosis factor (TNF) and interleukin 17A, and persisted in germ-free conditions. A20(ZF7) cells exhibited prolonged IKK kinase activity that drove exaggerated transcription of late-phase NF-κB-response genes in vitro and in pre-diseased mouse paws in vivo. In addition, mice expressing double-mutant A20 proteins in A20’s ZF4 and ZF7 motifs died perinatally with multi-organ inflammation. Therefore, A20’s ZF4 and ZF7 motifs synergistically prevent inflammatory disease in a non-catalytic manner.