Epstein-Barr virus-transforming protein latent infection membrane protein 1 activates transcription factor NF-kappaB through a pathway that includes the NF-kappaB-inducing kinase and the IkappaB kinases IKKalpha and IKKbeta.
The Epstein-Barr virus oncoprotein latent infection membrane protein 1 (LMP1) is a constitutively aggregated pseudo-tumor necrosis factor receptor (TNFR) that activates transcription factor NF-kappaB through two sites in its C-terminal cytoplasmic domain. One site is similar to activated TNFRII in associating with TNFR-associated factors TRAF1 and TRAF2, and the second site is similar to TNFRI in associating with the TNFRI death domain interacting protein TRADD. TNFRI has been recently shown to activate NF-kappaB through association with TRADD, RIP, and TRAF2; activation of the NF-kappaB-inducing kinase (NIK); activation of the IkappaB alpha kinases (IKKalpha and IKKbeta); and phosphorylation of IkappaB alpha. IkappaB alpha phosphorylation on Ser-32 and Ser-36 is followed by its degradation and NF-kappaB activation. In this report, we show that NF-kappaB activation by LMP1 or by each of its effector sites is mediated by a pathway that includes NIK, IKKalpha, and IKKbeta. Dominant negative mutants of NIK, IKKalpha, or IKKbeta substantially inhibited NF-kappaB activation by LMP1 or by each of its effector sites.
Sylla
B S
BS
Departments of Microbiology and Molecular Genetics and Medicine, Harvard Medical School and Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA.
Hung
S C
SC
Davidson
D M
DM
Hatzivassiliou
E
E
Malinin
N L
NL
Wallach
D
D
Gilmore
T D
TD
Kieff
E
E
Mosialos
G
G
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D006801:Humans; D051550:I-kappa B Kinase; D066298:In Vitro Techniques; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D012156:Reticulocytes / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D051550:I-kappa B Kinase; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D014763:Viral Matrix Proteins; D000097782:NF-kappaB-Inducing Kinase; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human