The Deubiquitinase Activity of A20 Is Dispensable for Its Role in NF-κB Signaling

Abstract

Ubiquitination of multiple signaling adaptor molecules by K63-linked ubiquitin chains have been proposed to be a key regulatory mechanism in NF-κB activation. Deubiquitinase enzymes such as A20 have been suggested to limit the persistence of NF-κB activation by removing regulatory ubiquitin chains from ubiquitinated substrates. A20 has garnered significant interest as mice lacking A20 die prematurely from multiorgan inflammation and cachexia, as a result of increased NF-κB signaling. Thus, it is evident that A20 is nonredundant in its ability to limit the persistence of NF-κB signaling. To understand the physiological relevance of A20-mediated deubiquitination, we generated knock-in mice that lack the deubiquitinating function of A20 (A20-OTU mice). We hypothesized that these mice would have an inflammatory phenotype because of increased, persistent NF-κB signaling. However our results show that A20 OUT mice display normal NF-κB activation and no inflammatory phenotype, thereby demonstrating that the deubiquitinase activity of A20 is dispensable for normal NF-κB signaling.