Deubiquitination of NF-κB by Ubiquitin-Specific Protease-7 promotes transcription

Abstract

NF-κB is the master regulator of the immune response and is responsible for the transcription of hundreds of genes controlling inflammation and immunity. Activation of NF-κB occurs in the cytoplasm through the kinase activity of the IκB kinase complex, which leads to translocation of NF-κB to the nucleus. Once in the nucleus, NF-κB transcriptional activity is regulated by DNA binding-dependent ubiquitin-mediated proteasomal degradation. We have identified the deubiquitinase Ubiquitin Specific Protease-7 (USP7) as a regulator of NF-κB transcriptional activity. USP7 deubiquitination of NF-κB leads to increased transcription. Loss of USP7 activity results in increased ubiquitination of NF-κB, leading to reduced promoter occupancy and reduced expression of target genes in response to Toll-like-and TNF-receptor activation. These findings reveal a unique mechanism controlling NF-κB activity and demonstrate that the deubiquitination of NF-κB by USP7 is critical for target gene transcription.

Deubiquitination of Tip60 by USP7 Determines the Activity of the p53-Dependent Apoptotic Pathway

“…7G). Alternatively, the deubiquitination activity of USP7 is also required for the stability of other proteins such as PTEN, Claspin, FOXO4, UHRF1, and NF-B (42)(43)(44)(45)(46). It is therefore also possible that the residual cytotoxicity of P22077 in cells overexpressing Flag-Tip60 is due to a decrease of the levels of these other cellular targets of USP7.…”

Ubiquitination in the antiviral immune response

“…PDLIM2 binds to p65 and induces its specific relocation to PML-containing intranuclear compartments where p65 undergoes K48-linked ubiquitination and degradation by the 26S proteasome [167]. USP7 has been reported to counteract p65 degradation through removal of K48-linked ubiquitin chains [168]. …”

Inhibition of Transcription by B Cell Leukemia 3 (Bcl-3) Protein Requires Interaction with Nuclear Factor κB (NF-κB) p50

“…Specifically, a library of overlapping peptides 18 amino acids in length, each shifted by three amino acids and encompassing the entire sequence of p50, was SPOT-synthesized on nitrocellulose membranes to generate p50 arrays. Peptide arrays were overlaid with purified recombinant GST or GST-Bcl-3 protein and, following extensive washing, probed with anti-GST antibody as described previously (23,24,25). The suitability of GST-Bcl-3 for use as a p50 peptide library probe was established using a GST pulldown assay in which purified GST-Bcl-3, but not GST, bound to p50 (Fig.…”