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LIND/ABIN-3 is a novel lipopolysaccharide-inducible inhibitor of NF-kappaB activation.

Recognition of lipopolysaccharide (LPS) by Toll-like receptor (TLR)4 initiates an intracellular signaling pathway leading to the activation of nuclear factor-kappaB (NF-kappaB). Although LPS-induced activation of NF-kappaB is critical to the induction of an efficient immune response, excessive or prolonged signaling from TLR4 can be harmful to the host. Therefore, the NF-kappaB signal transduction pathway demands tight regulation. In the present study, we describe the human protein Listeria INDuced (LIND) as a novel A20-binding inhibitor of NF-kappaB activation (ABIN) that is related to ABIN-1 and -2 and, therefore, is further referred to as ABIN-3. Similar to the other ABINs, ABIN-3 binds to A20 and inhibits NF-kappaB activation induced by tumor necrosis factor, interleukin-1, and 12-O-tetradecanoylphorbol-13-acetate. However, unlike the other ABINs, constitutive expression of ABIN-3 could not be detected in different human cells. Treatment of human monocytic cells with LPS strongly induced ABIN-3 mRNA and protein expression, suggesting a role for ABIN-3 in the LPS/TLR4 pathway. Indeed, ABIN-3 overexpression was found to inhibit NF-kappaB-dependent gene expression in response to LPS/TLR4 at a level downstream of TRAF6 and upstream of IKKbeta. NF-kappaB inhibition was mediated by the ABIN-homology domain 2 and was independent of A20 binding. Moreover, in vivo adenoviral gene transfer of ABIN-3 in mice reduced LPS-induced NF-kappaB activity in the liver, thereby partially protecting mice against LPS/D-(+)-galactosamine-induced mortality. Taken together, these results implicate ABIN-3 as a novel negative feedback regulator of LPS-induced NF-kappaB activation.

Pubmed ID: 17088249

Authors

  • Wullaert A
  • Verstrepen L
  • Van Huffel S
  • Adib-Conquy M
  • Cornelis S
  • Kreike M
  • Haegman M
  • El Bakkouri K
  • Sanders M
  • Verhelst K
  • Carpentier I
  • Cavaillon JM
  • Heyninck K
  • Beyaert R

Journal

The Journal of biological chemistry

Publication Data

January 5, 2007

Associated Grants

None

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • DNA-Binding Proteins
  • Gene Expression Regulation
  • Humans
  • Lipopolysaccharides
  • Listeria
  • Molecular Sequence Data
  • Monocytes
  • NF-kappa B
  • Protein Binding
  • Proteins
  • RNA, Messenger
  • Sequence Homology, Amino Acid
  • Toll-Like Receptor 4