TNAP, a novel repressor of NF-kappaB-inducing kinase, suppresses NF-kappaB activation.
NF-kappaB-inducing kinase (NIK) has been implicated as an essential component of NF-kappaB activation. However, the regulatory mechanism of NIK signaling remains elusive. We have identified a novel NIK interacting protein, TNAP (for TRAFs and NIK-associated protein). In mammalian cells, TNAP physically interacts with NIK, TRAF2, and TRAF3 but not IKK1 or IKK2. TNAP specifically inhibits NF-kappaB activation induced by tumor necrosis factor (TNF)-alpha, TNF receptor 1, TRADD, RIP, TRAF2, and NIK but does not affect IKK1- and IKK2-mediated NF-kappaB activation. Knockdown of TNAP by lentiviral-mediated small interference RNA potentiates TNF-alpha-induced NF-kappaB activation. TNAP suppresses NIK kinase activity and subsequently reduces p100 processing, p65 phosphorylation, and IkappaBalpha degradation. These data suggest that TNAP is a repressor of NIK activity and regulates both the classical and alternative NF-kappaB signaling pathways.
Hu
Wen-Hui
WH
Miami Project to Cure Paralysis, University of Miami School of Medicine, Miami, Florida 33136, USA.
Mo
Xian-Ming
XM
Walters
Winston M
WM
Brambilla
Roberta
R
Bethea
John R
JR
D000469:Alkaline Phosphatase; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003001:Cloning, Molecular; D004789:Enzyme Activation; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D000469:Alkaline Phosphatase; D002352:Carrier Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D012097:Repressor Proteins; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D000097782:NF-kappaB-Inducing Kinase; C548267:ALPL protein, human