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.
Wullaert
Andy
A
Unit of Molecular Signal Transduction in Inflammation, Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology, Ghent University, Belgium.
Verstrepen
Lynn
L
Van Huffel
Sofie
S
Adib-Conquy
Minou
M
Cornelis
Sigrid
S
Kreike
Marja
M
Haegman
Mira
M
El Bakkouri
Karim
K
Sanders
Matthew
M
Verhelst
Kelly
K
Carpentier
Isabelle
I
Cavaillon
Jean-Marc
JM
Heyninck
Karen
K
Beyaert
Rudi
R
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
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