title: COMMD7 as a novel NEMO interacting protein involved in the termination of NF-κB signaling.
abstract: NEMO/IKKγ is the regulatory subunit of the IκB Kinase (IKK) complex, required for the activation of the NF-κB pathway, which is involved in a variety of key processes, including immunity, inflammation, differentiation, and cell survival. Termination of NF-κB activity on specific -κB responsive genes, which is crucial for the resolution of inflammatory responses, can be achieved by direct degradation of the chromatin-bound NF-κB 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-κB activation upon TNFα stimulation. COMMD7 interacts with COMMD1 and together they cooperate to down-regulate NF-κB activity. Accordingly, termination of TNFα-induced NF-κB activity on the -κB 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 TNFα-induced NF-κB 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-κB activity. We propose that an intact IKK complex is required for the termination of NF-κB-dependent transcription and that COMMD7 acts as a scaffold in the IKK-mediated NF-κB termination.
authors.affiliation: Institute of Genetics and Biophysics, 'Adriano Buzzati-Traverso' (CNR), Naples, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Esposito
authors.affiliation: Institute of Genetics and Biophysics, 'Adriano Buzzati-Traverso' (CNR), Naples, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Napolitano
authors.affiliation: Institute of Genetics and Biophysics, 'Adriano Buzzati-Traverso' (CNR), Naples, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pescatore
authors.affiliation: Institute of Genetics and Biophysics, 'Adriano Buzzati-Traverso' (CNR), Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Calculli
authors.affiliation: IRCCS SDN, Via E. Gianturco 113, Naples, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Incoronato
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, "Federico II" University of Naples, via S. Pansini 5, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Leonardi
authors.affiliation: Institute of Genetics and Biophysics, 'Adriano Buzzati-Traverso' (CNR), Naples, Italy.|IRCCS SDN, Via E. Gianturco 113, Naples, Italy.
authors.forename: Matilde Valeria
authors.initials: MV
authors.lastname: Ursini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C554642:COMMD7 protein, human; C491731:IKBKG protein, human; D016328:NF-kappa B; D051550:I-kappa B Kinase