NEMO: An Adaptive Regulator

Abstract

STKE Nuclear factor κB (NF-κB), a transcription factor critical in the immune response to pathogens, is maintained in the inactive state by an inhibitory protein (IκB). The IκB kinase (IKK) complex activates NF-κB by dissociating IκB, and NEMO, also known as IKKγ, is a regulatory subunit of this complex. Zhao et al. show that in addition to this role in NF-κB activation, NEMO helps to activate the interferon regulatory factors IRF3 and IRF7, which, in combination with NF-κB and activator protein 1, stimulate the transcription of type I interferons (IFN-α and -β) in virally infected cells. Experiments with mouse embryo fibroblasts deficient in the gene encoding NEMO showed that the efficient production of IFN-α and the subsequent expression of signal transducer and activator of transcription 1 (STAT1) required NEMO, but not IKKβ (a subunit required for NF-κB activation), suggesting that NEMO was not acting through the NF-κB pathway. Reporter gene assays also demonstrated the dependence of IRF3- and IRF7-mediated gene expression on NEMO. In the NEMO knockout cells, overexpression of TBK1 (an IKK-related kinase that is upstream of IRF3 and IRF7 activation) restored reporter gene activation, and NEMO was also required for activation of the kinase activity of TBK1, placing NEMO upstream of TBK1 in the path to IRF3 and IRF7 activation. However, NEMO did not interact directly with TBK1 (or the related kinase IKKϵ); instead, immunoprecipitation studies with transfected cells showed that TANK (TRAF family member-associated NF-κB activator) was required for the formation of a trimeric complex of TANK, NEMO, and either IKKϵ or TBK1. Mutational and deletion analyses suggest that different regions of NEMO participate in NF-κB versus IRF activation. — NRG Nat. Immunol. 8 , 592 (2007).