COMMD1 promotes the ubiquitination of NF-κB subunits through a cullin-containing ubiquitin ligase
Copyright policy )COMMD1 promotes the ubiquitination of NF-κB 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.
- University of Michigan–Flint United States
- Veterans Health Administration United States
- VA Ann Arbor Healthcare System United States
- University of Michigan–Ann Arbor United States
- Ann Arbor VA Medical Center United States
Protein Denaturation, Ubiquitin-Protein Ligases, Elongin, Suppressor of Cytokine Signaling Proteins, Models, Biological, Cullin, Suppressor of Cytokine Signaling 1 Protein, Health Sciences, Humans, Gene Silencing, Cellular and Developmental Biology, Cells, Cultured, Adaptor Proteins, Signal Transducing, Cell Nucleus, Ubiquitin, NF‐κB, Ubiquitination, NF-kappa B, Transcription Factor RelA, Molecular, Proteins, COMMD1, Cullin Proteins, Protein Subunits, Carrier Proteins, Transcription, Protein Binding, Transcription Factors
Protein Denaturation, Ubiquitin-Protein Ligases, Elongin, Suppressor of Cytokine Signaling Proteins, Models, Biological, Cullin, Suppressor of Cytokine Signaling 1 Protein, Health Sciences, Humans, Gene Silencing, Cellular and Developmental Biology, Cells, Cultured, Adaptor Proteins, Signal Transducing, Cell Nucleus, Ubiquitin, NF‐κB, Ubiquitination, NF-kappa B, Transcription Factor RelA, Molecular, Proteins, COMMD1, Cullin Proteins, Protein Subunits, Carrier Proteins, Transcription, Protein Binding, Transcription Factors
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