A role for NF-κB essential modifier/IκB kinase-γ (NEMO/IKKγ) ubiquitination in the activation of the IκB kinase complex by tumor necrosis factor-α

Abstract

NEMO (NF-κB essential modifier)/IKKγ (IκB kinase-γ) is required for the activation of the IκB kinase complex (IKK) by inflammatory stimuli such as tumor necrosis factor (TNF-α). Here we show that TNF-α stimulates the ubiquitination of NEMO in a manner that does not appear to target it for degradation and that is impaired by mutations in the NEMO zinc finger. Mutations of the zinc finger are found in patients with hypohidrotic ectodermal dysplasia with immunodeficiency (HED-ID) and lead to the impairment of TNF-α-stimulated IKK phosphorylation and activation. In addition, the ubiquitination of NEMO is mediated by c-IAP1, an inhibitor of apoptosis protein that is a component of the TNF receptor signaling complex. Thus, the ubiquitination of NEMO mediated by c-IAP1 likely plays an important role in the activation of IKK by TNF-α. Also, defective NEMO ubiquitination may be responsible for the impaired cellular NF-κB signaling found in patients with HED-ID.