CARMA3 deficiency abrogates G protein-coupled receptor-induced NF-κB activation
- Brian C. Grabiner1,5,
- Marzenna Blonska1,5,
- Pei-Chun Lin1,
- Yun You1,
- Donghai Wang4,
- Jiyuan Sun1,
- Bryant G. Darnay2,
- Chen Dong3, and
- Xin Lin1,6
- 1 Department of Molecular and Cellular Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
- 2 Department of Experimental Therapeutics, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
- 3 Department of Immunology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
- 4 The CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts 02115, USA
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↵5 These authors contributed equally to this work.
Abstract
G protein-coupled receptors (GPCRs) play pivotal roles in regulating various cellular functions. Although many GPCRs induce NF-κB activation, the molecular mechanism of GPCR-induced NF-κB activation remains largely unknown. CARMA3 (CARD and MAGUK domain-containing protein 3) is a scaffold molecule with unknown biological functions. By generating CARMA3 knockout mice using the gene targeting approach, here we show CARMA3 is required for GPCR-induced NF-κB activation. Mechanistically, we found that CARMA3 deficiency impairs GPCR-induced IκB kinase (IKK) activation, although it does not affect GPCR-induced IKKα/β phosphorylation, indicating that inducible phosphorylation of IKKα/β alone is not sufficient to induce its kinase activity. We also found that CARMA3 is physically associated with NEMO/IKKγ, and induces polyubiquitination of an unknown protein(s) that associates with NEMO, likely by linking NEMO to TRAF6. Consistently, we found TRAF6 deficiency also abrogates GPCR-induced NF-κB activation. Together, our results provide the genetic evidence that CARMA3 is required for GPCR-induced NF-κB activation.
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Footnotes
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↵6 Corresponding author.
↵6 E-MAIL xllin{at}mdanderson.org; FAX (713) 794-0209.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1502507
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- Received October 13, 2006.
- Accepted February 20, 2007.
- Copyright © 2007, Cold Spring Harbor Laboratory Press