Activation of NF-kappaB by hepatitis B virus X protein through an IkappaB kinase-independent mechanism.
pX, the hepatitis B virus-encoded transcription coactivator, is involved in viral infection in vivo. pX stimulates the activity of several transcription factors including nuclear factor-kappaB (NF-kappaB), but the mechanism of activation is poorly understood. The IkappaB kinase complex (IKK) mediates activation of NF-kappaB in response to various extracellular stimuli, including inflammatory cytokines like tumor necrosis factor and interleukin 1, human T cell lymphoma virus 1 Tax protein, and tumor promoters like phorbol esters. It is not known whether IKK also mediates activation of NF-kappaB by pX. Here we report that IKK was not essential for activation of NF-kappaB by pX. Expression of pX resulted in the degradation of IkappaBalpha in the absence of its phosphorylation at Ser(32) and Ser(36) residues. Although pX stimulated the activity of cotransfected IKK-beta when it was overexpressed, it failed to activate endogenous IKK. Furthermore, expression of pX stimulated NF-kappaB nuclear translocation and transcriptional activity in IKK-gamma-null fibroblast 5R cells. Our data indicate that pX stimulates NF-kappaB activity through a mechanism that is dependent on IkappaBalpha degradation but not on IKK activation.
Ben May Institute for Cancer Research, Committee on Cancer Biology, University of Chicago, Chicago, Illinois 60637, USA.
N H
NH
Purcell
C
C
Yu
D
D
He
J
J
Xiang
N
N
Paran
J A
JA
DiDonato
S
S
Yamaoka
Y
Y
Shaul
A
A
Lin
D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005347:Fibroblasts; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D015151:Immunoblotting; D008099:Liver / Q000166:cytology; D009097:Multienzyme Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects*; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015534:Trans-Activators / Q000494:pharmacology*; D014158:Transcription, Genetic; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins
D009097:Multienzyme Complexes; D016328:NF-kappa B; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex