title: LIND/ABIN-3 is a novel lipopolysaccharide-inducible inhibitor of NF-kappaB activation.
abstract: 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.
authors.affiliation: Unit of Molecular Signal Transduction in Inflammation, Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology, Ghent University, Belgium.
authors.forename: Andy
authors.initials: A
authors.lastname: Wullaert
authors.forename: Lynn
authors.initials: L
authors.lastname: Verstrepen
authors.forename: Sofie
authors.initials: S
authors.lastname: Van Huffel
authors.forename: Minou
authors.initials: M
authors.lastname: Adib-Conquy
authors.forename: Sigrid
authors.initials: S
authors.lastname: Cornelis
authors.forename: Marja
authors.initials: M
authors.lastname: Kreike
authors.forename: Mira
authors.initials: M
authors.lastname: Haegman
authors.forename: Karim
authors.initials: K
authors.lastname: El Bakkouri
authors.forename: Matthew
authors.initials: M
authors.lastname: Sanders
authors.forename: Kelly
authors.initials: K
authors.lastname: Verhelst
authors.forename: Isabelle
authors.initials: I
authors.lastname: Carpentier
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Cavaillon
authors.forename: Karen
authors.initials: K
authors.lastname: Heyninck
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry; D000595:Amino Acid Sequence; D004268:DNA-Binding Proteins / Q000737:chemistry; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000378:metabolism*; D008087:Listeria / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011506:Proteins; D012333:RNA, Messenger; C495345:TLR4 protein, human; C117046:TNIP1 protein, human; C434062:TNIP2 protein, human; C426747:TNIP3 protein, human; D051197:Toll-Like Receptor 4