COMMD7 as a novel NEMO interacting protein involved in the termination of NF kB signaling
NEMO/IKKg is the regulatory subunit of the IkB Kinase (IKK) complex, required for the activation of the NF kB pathway, which is involved in a variety of key processes, including immunity, inflammation, differentiation, and cell survival. Termination of NF kB activity on specific kB responsive genes, which is crucial for the resolution of inflammatory responses, can be achieved by direct degradation of the chromatin bound NF kB subunit RelA/p65, a process mediated by a protein complex that contains Copper Metabolism Murr1 Domain 1 (COMMD1) In this study, we identify COMMD7, another member of the COMMDs protein family, as a novel NEMO interacting protein. We show that COMMD7 exerts an inhibitory effect on NF kB activation upon TNFa stimulation. COMMD7 interacts with COMMD1 and together they cooperate to down regulate NF kB activity. Accordingly, termination of TNFa induced NF kB activity on the kB responsive gene, Icam1, is defective in cells silenced for COMMD7 expression. Furthermore, this impairment is not greatly increased when we silence the expression of both COMMD7 and COMMD1 indicating that the two proteins participate in the same pathway of termination of TNFa induced NF kB activity. Importantly, we have demonstrated that COMMD7's binding to NEMO does not interfere with the binding to the IKKs, and that the disruption of the IKK complex through the use of the NBP competitor impairs the termination of NF kB activity. We propose that an intact IKK complex is required for the termination of NF kB dependent transcription and that COMMD7 acts as a scaffold in the IKK mediated NF kB termination. J. Cell. Physiol. 230: 152 161, 2016. (c) 2015 Wiley Periodicals, Inc.
Journal of cellular physiology