title: Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation.
abstract: The NF-kappaB family of transcription factors plays a pivotal role in regulation of diverse biological processes, including immune responses, cell growth, and apoptosis. Activation of NF-kappaB is mediated by both canonical and noncanonical signaling pathways. Although the canonical pathway has been extensively studied, the mechanism mediating the noncanonical pathway is still poorly understood. Recent studies have identified the NF-kappaB-inducing kinase (NIK) as a key component of the noncanonical pathway of NF-kappaB activation; however, how the signaling function of NIK is regulated remains unknown. We report here that one important mechanism of NIK regulation is through its dynamic interaction with the tumor necrosis factor receptor-associated factor 3 (TRAF3). TRAF3 physically associates with NIK via a specific sequence motif located in the N-terminal region of NIK; this molecular interaction appears to target NIK for degradation by the proteasome. Interestingly, induction of noncanonical NF-kappaB signaling by extracellular signals involves degradation of TRAF3 and the concomitant enhancement of NIK expression. These results suggest that induction of noncanonical NF-kappaB signaling may involve the rescue of NIK from TRAF3-mediated negative regulation.
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Gongxian
authors.initials: G
authors.lastname: Liao
authors.forename: Minying
authors.initials: M
authors.lastname: Zhang
authors.forename: Edward W
authors.initials: EW
authors.lastname: Harhaj
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
mesh_terms: D020816:Amino Acid Motifs; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015151:Immunoblotting; D009097:Multienzyme Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D012190:Retroviridae; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3; D014162:Transfection; D020798:Two-Hybrid System Techniques; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D003546:Cysteine Endopeptidases; D018076:DNA, Complementary; D009097:Multienzyme Complexes; D016328:NF-kappa B; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D048008:TNF Receptor-Associated Factor 3; D000097782:NF-kappaB-Inducing Kinase