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PMID: 10648614 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

NF-kappaB activation by double-stranded-RNA-activated protein kinase (PKR) is mediated through NF-kappaB-inducing kinase and IkappaB kinase.

Molecular and cellular biology ·Vol. 20 ·No. 4 ·2000-02-00 ·Pages 1278-90

Zamanian-Daryoush M, Mogensen TH, DiDonato JA, Williams BR

Abstract

The interferon (IFN)-inducible double-stranded-RNA (dsRNA)-activated serine-threonine protein kinase (PKR) is a major mediator of the antiviral and antiproliferative activities of IFNs. PKR has been implicated in different stress-induced signaling pathways including dsRNA signaling to nuclear factor kappa B (NF-kappaB). The mechanism by which PKR mediates activation of NF-kappaB is unknown. Here we show that in response to poly(rI). poly(rC) (pIC), PKR activates IkappaB kinase (IKK), leading to the degradation of the inhibitors IkappaBalpha and IkappaBbeta and the concomitant release of NF-kappaB. The results of kinetic studies revealed that pIC induced a slow and prolonged activation of IKK, which was preceded by PKR activation. In PKR null cell lines, pIC failed to stimulate IKK activity compared to cells from an isogenic background wild type for PKR in accord with the inability of PKR null cells to induce NF-kappaB in response to pIC. Moreover, PKR was required to establish a sustained response to tumor necrosis factor alpha (TNF-alpha) and to potentiate activation of NF-kappaB by cotreatment with TNF-alpha and IFN-gamma. By coimmunoprecipitation, PKR was shown to be physically associated with the IKK complex. Transient expression of a dominant negative mutant of IKKbeta or the NF-kappaB-inducing kinase (NIK) inhibited pIC-induced gene expression from an NF-kappaB-dependent reporter construct. Taken together, these results demonstrate that PKR-dependent dsRNA induction of NF-kappaB is mediated by NIK and IKK activation.

MeSH Terms
Animals Cell Line Enzyme Activation/drug effects Humans I-kappa B Kinase Kinetics Mice Mice, Knockout NF-kappa B/metabolism Poly I-C/pharmacology Protein Serine-Threonine Kinases/metabolism RNA, Double-Stranded/metabolism Signal Transduction Transfection Tumor Necrosis Factor-alpha/pharmacology eIF-2 Kinase/genetics,metabolism
Chemicals
NF-kappa B RNA, Double-Stranded Tumor Necrosis Factor-alpha Protein Serine-Threonine Kinases eIF-2 Kinase CHUK protein, human Chuk protein, mouse I-kappa B Kinase IKBKB protein, human IKBKE protein, human Ikbkb protein, mouse Ikbke protein, mouse NF-kappa B kinase Poly I-C
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Zamanian-Daryoush M
Department of Cancer Biology, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Mogensen T H
DiDonato J A
Williams B R
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.20.4.1278-1290.2000
Published
2000-02-00
Pages
1278-90
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC85265
Subset
IM
Grants
NIAID NIH HHS · R01 AI034039 · United States
NIAID NIH HHS · AI34039 · United States
External Links
PubMed source DOI: 10.1128/MCB.20.4.1278-1290.2000 PMC Full Text View journal details
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