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Molecular and Cellular Biology, July 2000, p. 4532-4542, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

PKR Stimulates NF-kappa B Irrespective of Its Kinase Function by Interacting with the Ikappa B Kinase Complex

Marion C. Bonnet,1 Robert Weil,2 Elisabeth Dam,1 Ara G. Hovanessian,1 and Eliane F. Meurs1,*

Unité de Virologie et d'Immunologie Cellulaire, URA CNRS 1930,1 and Unité de Biologie Moléculaire de l'Expression Génique, URA 1773 CNRS,2 Institut Pasteur, 75724 Paris Cedex 15, France

Received 11 February 2000/Returned for modification 21 March 2000/Accepted 27 March 2000

The interferon (IFN)-induced double-stranded RNA-activated protein kinase PKR mediates inhibition of protein synthesis through phosphorylation of the alpha  subunit of eukaryotic initiation factor 2 (eIF2alpha ) and is also involved in the induction of the IFN gene through the activation of the transcription factor NF-kappa B. NF-kappa B is retained in the cytoplasm through binding to its inhibitor Ikappa Balpha . The critical step in NF-kappa B activation is the phosphorylation of Ikappa Balpha by the Ikappa B kinase (IKK) complex. This activity releases NF-kappa B from Ikappa Balpha and allows its translocation to the nucleus. Here, we have studied the ability of PKR to activate NF-kappa B in a reporter assay and have shown for the first time that two catalytically inactive PKR mutants, PKR/KR296 and a deletion mutant (PKR/Del42) which lacks the potential eIF2alpha -binding domain, can also activate NF-kappa B. This result indicated that NF-kappa B activation by PKR does not require its kinase activity and that it is independent of the PKR-eIF2alpha relationship. Transfection of either wild-type PKR or catalytically inactive PKR in PKR0/0 mouse embryo fibroblasts resulted in the activation of the IKK complex. By using a glutathione S-transferase pull-down assay, we showed that PKR interacts with the IKKbeta subunit of the IKK complex. This interaction apparently does not require the integrity of the IKK complex, as it was found to occur with extracts from cells deficient in the NF-kappa B essential modulator, one of the components of the IKK complex. Therefore, our results reveal a novel pathway by which PKR can modulate the NF-kappa B signaling pathway without using its kinase activity.

* Corresponding author. Mailing address: Unité de Virologie et d'Immunologie Cellulaire, URA CNRS 1930, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France. Phone: 33 01 45 68 87 77. Fax: 33 01 40 61 30 12. E-mail: emeurs{at}pasteur.fr.

Molecular and Cellular Biology, July 2000, p. 4532-4542, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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