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Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation.

Nuclear factor-kappaB (NF-kappaB) is a key transcription factor in inflammatory, anti-apoptotic and immune processes. The ubiquitin pathway is crucial in regulating the NF-kappaB pathway. We have found that the LUBAC ligase complex, composed of the two RING finger proteins HOIL-1L and HOIP, conjugates a head-to-tail-linked linear polyubiquitin chain to substrates. Here, we demonstrate that LUBAC activates the canonical NF-kappaB pathway by binding to NEMO (NF-kappaB essential modulator, also called IKKgamma) and conjugates linear polyubiquitin chains onto specific Lys residues in the CC2-LZ domain of NEMO in a Ubc13-independent manner. Moreover, in HOIL-1 knockout mice and cells derived from these mice, NF-kappaB signalling induced by pro-inflammatory cytokines such as TNF-alpha and IL-1beta was suppressed, resulting in enhanced TNF-alpha-induced apoptosis in hepatocytes of HOIL-1 knockout mice. These results indicate that LUBAC is involved in the physiological regulation of the canonical NF-kappaB activation pathway through linear polyubiquitylation of NEMO.

Pubmed ID: 19136968

Authors

  • Tokunaga F
  • Sakata S
  • Saeki Y
  • Satomi Y
  • Kirisako T
  • Kamei K
  • Nakagawa T
  • Kato M
  • Murata S
  • Yamaoka S
  • Yamamoto M
  • Akira S
  • Takao T
  • Tanaka K
  • Iwai K

Journal

Nature cell biology

Publication Data

February 3, 2009

Associated Grants

None

Mesh Terms

  • Animals
  • Apoptosis
  • Carrier Proteins
  • Cell Line
  • Chimera
  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • Macromolecular Substances
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Knockout
  • Molecular Structure
  • NF-kappa B
  • Polymers
  • RING Finger Domains
  • Ubiquitin
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligases
  • Ubiquitination