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Interleukin-1-induced NF-kappaB activation is NEMO-dependent but does not require IKKbeta.

Activation of NF-kappaB by the pro-inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) requires the IkappaB kinase (IKK) complex, which contains two kinases named IKKalpha and IKKbeta and a critical regulatory subunit named NEMO. Although we have previously demonstrated that NEMO associates with both IKKs, genetic studies reveal that only its interaction with IKKbeta is required for TNF-induced NF-kappaB activation. To determine whether NEMO and IKKalpha can form a functional IKK complex capable of activating the classical NF-kappaB pathway in the absence of IKKbeta, we utilized a panel of mouse embryonic fibroblasts (MEFs) lacking each of the IKK complex subunits. This confirmed that TNF-induced IkappaBalpha degradation absolutely requires NEMO and IKKbeta. In contrast, we consistently observed intact IkappaBalpha degradation and NF-kappaB activation in response to IL-1 in two separate cell lines lacking IKKbeta. Furthermore, exogenously expressed, catalytically inactive IKKbeta blocked TNF- but not IL-1-induced IkappaBalpha degradation in wild-type MEFs, and reconstitution of IKKalpha/beta double knockout cells with IKKalpha rescued IL-1- but not TNF-induced NF-kappaB activation. Finally, we have shown that incubation of IKKbeta-deficient MEFs with a cell-permeable peptide that blocks the interaction of NEMO with the IKKs inhibits IL-1-induced NF-kappaB activation. Our results therefore demonstrate that NEMO and IKKalpha can form a functional IKK complex that activates the classical NF-kappaB pathway in response to IL-1 but not TNF. These findings further suggest NEMO differentially regulates the fidelity of the IKK subunits activated by distinct upstream signaling pathways.

Pubmed ID: 17244613

Authors

  • Solt LA
  • Madge LA
  • Orange JS
  • May MJ

Journal

The Journal of biological chemistry

Publication Data

March 23, 2007

Associated Grants

  • Agency: NHLBI NIH HHS, Id: 1R01HL080612-01A1
  • Agency: NIAID NIH HHS, Id: N01AI-22070
  • Agency: NHLBI NIH HHS, Id: R01 HL080612
  • Agency: NHLBI NIH HHS, Id: R01 HL080612-01A1

Mesh Terms

  • Animals
  • Catalysis
  • Cell Line
  • Enzyme Activation
  • Gene Expression Regulation
  • Humans
  • I-kappa B Kinase
  • Interleukin-1
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • NF-kappa B
  • Peptides
  • Protein Binding
  • Recombinant Proteins
  • Signal Transduction