CARMA3 deficiency abrogates G protein-coupled receptor-induced NF-κB activation

Brian C. Grabiner, Marzenna Blonska, Pei Chun Lin, Yun You, Donghai Wang, Jiyuan Sun, Bryant G. Darnay, Chen Dong, Xin Lin

Research output: Contribution to journalArticle

89 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)984-996
Number of pages13
JournalGenes and Development
Volume21
Issue number8
DOIs
StatePublished - Apr 15 2007
Externally publishedYes

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Keywords

  • CARMA3
  • GPCR
  • NF-κB
  • Neural tube

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Grabiner, B. C., Blonska, M., Lin, P. C., You, Y., Wang, D., Sun, J., Darnay, B. G., Dong, C., & Lin, X. (2007). CARMA3 deficiency abrogates G protein-coupled receptor-induced NF-κB activation. Genes and Development, 21(8), 984-996. https://doi.org/10.1101/gad.1502507