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Deubiquitination of NF-κB by Ubiquitin-Specific Protease-7 promotes transcription
- Colleran, Amy, Collins, Patricia E., O’Carroll, Christine, Ahmed, Abrar, Mao, Xicheng, McManus, Bettina, Kiely, Patrick A., Burstein, Ezra, Carmody, Ruaidhrí J.
- Proceedings of the National Academy of Sciences of the United States of America 2013 v.110 no.2 pp. 618-623
- DNA, cytoplasm, genes, immune response, inflammation, transcription (genetics), transcription factor NF-kappa B, ubiquitin, ubiquitination
- 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.