Mechanisms of Signal Transduction
Ubiquitin-specific Peptidase 21 Inhibits Tumor Necrosis Factor α-induced Nuclear Factor κB Activation via Binding to and Deubiquitinating Receptor-interacting Protein 1*

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Ubiquitination and deubiquitination of receptor-interacting protein 1 (RIP1) play an important role in the positive and negative regulation of the tumor necrosis factor α (TNFα)-induced nuclear factor κB (NF-κB) activation. Using a combination of functional genomic and proteomic approaches, we have identified ubiquitin-specific peptidase 21 (USP21) as a deubiquitinase for RIP1. USP21 is constitutively associated with RIP1 and deubiquitinates RIP1 in vitro and in vivo. Notably, knockdown of USP21 in HeLa cells enhances TNFα-induced RIP1 ubiquitination, IκB kinase β (IKKβ), and NF-κB phosphorylation, inhibitor of NF-κB α (IκBα) phosphorylation and ubiquitination, as well as NF-κB-dependent gene expression. Therefore, our results demonstrate that USP21 plays an important role in the down-regulation of TNFα-induced NF-κB activation through deubiquitinating RIP1.

Cytokines/Tumor Necrosis Factor
Enzymes/Peptidases
Receptors/Cytokine
Signal Transduction
Signal Transduction/Protein Kinases/MAP
Signal Transduction/Protein Kinases/Serine/Threonine
Transcription/NF-κB

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*

This work was supported, in whole or in part, by National Institutes of Health Grant 1R21CA106513-01A2 (to J. Y.), American Cancer Society Grant RSG-06-070-01-TBE (to J. Y.), and National Basic Research Program of China Grant 2007CB511900 (to T. Z.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Figs. S1–S3.

1

Both authors contributed equally to this work.