Adipocyte enhancer-binding protein-1 promotes macrophage inflammatory responsiveness by up-regulating NF-kappaB via IkappaBalpha negative regulation.
Nuclear factor kappaB (NF-kappaB) subunits comprise a family of eukaryotic transcription factors that are critically involved in cell proliferation, inflammation, and apoptosis. Under basal conditions, NF-kappaB subunits are kept under inhibitory regulation by physical interaction with NF-kappaB inhibitors (IkappaB subunits) in the cytosol. Upon stimulation, IkappaB subunits become phosphorylated, ubiquitinated, and subsequently degraded, allowing NF-kappaB subunits to translocate to the nucleus and bind as dimers to kappaB responsive elements of target genes. Previously, we have shown that AEBP1 enhances macrophage inflammatory responsiveness by inducing the expression of various proinflammatory mediators. Herein, we provide evidence suggesting that AEBP1 manifests its proinflammatory function by up-regulating NF-kappaB activity via hampering IkappaBalpha, but not IkappaBbeta, inhibitory function through protein-protein interaction mediated by the discoidin-like domain (DLD) of AEBP1. Such interaction renders IkappaBalpha susceptible to enhanced phosphorylation and degradation, subsequently leading to augmented NF-kappaB activity. Collectively, we propose a novel molecular mechanism whereby NF-kappaB activity is modulated by means of protein-protein interaction involving AEBP1 and IkappaBalpha. Moreover, our study provides a plausible mechanism explaining the differential regulatory functions exhibited by IkappaBalpha and IkappaBbeta in various cell types. We speculate that AEBP1 may serve as a potential therapeutic target for the treatment of various chronic inflammatory diseases and cancer.
Majdalawieh
Amin
A
Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5.
Zhang
Lei
L
Ro
Hyo-Sung
HS
D041721:3T3-L1 Cells; D000818:Animals; D002268:Carboxypeptidases / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation; D007700:Kinetics; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013816:Thermodynamics; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics*
C112918:Aebp1 protein, mouse; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D012097:Repressor Proteins; D000072000:NF-KappaB Inhibitor alpha; D002268:Carboxypeptidases