COMMD1 promotes the ubiquitination of NF-kappaB subunits through a cullin-containing ubiquitin ligase.
NF-kappaB is a pleiotropic transcription factor involved in multiple processes, including inflammation and oncogenesis. We have previously reported that COMMD1 represses kappaB-dependent transcription by negatively regulating NF-kappaB-chromatin interactions. Recently, ubiquitination of NF-kappaB subunits has been similarly implicated in the control of NF-kappaB recruitment to chromatin. We report here that COMMD1 accelerates the ubiquitination and degradation of NF-kappaB subunits through its interaction with a multimeric ubiquitin ligase containing Elongins B and C, Cul2 and SOCS1 (ECS(SOCS1)). COMMD1-deficient cells demonstrate stabilization of RelA, greater nuclear accumulation of RelA after TNF stimulation, de-repression of several kappaB-responsive genes, and enhanced NF-kappaB-mediated cellular responses. COMMD1 binds to Cul2 in a stimulus-dependent manner and serves to facilitate substrate binding to the ligase by stabilizing the interaction between SOCS1 and RelA. Our data uncover that ubiquitination and degradation of NF-kappaB subunits by this COMMD1-containing ubiquitin ligase is a novel and critical mechanism of regulation of NF-kappaB-mediated transcription.
Maine
Gabriel N
GN
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Mao
Xicheng
X
Komarck
Christine M
CM
Burstein
Ezra
E
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000378:metabolism*; D000075065:Elongin; D020868:Gene Silencing; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D011489:Protein Denaturation; D021122:Protein Subunits / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C480519:COMMD1 protein, human; C105153:CUL2 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; D000075065:Elongin; D016328:NF-kappa B; D021122:Protein Subunits; D011506:Proteins; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051996:Transcription Factor RelA; D014157:Transcription Factors; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases