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Molecular and Cellular Biology, July 1999, p. 4653-4663, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Induction of Apoptosis by Double-Stranded-RNA-Dependent Protein Kinase (PKR) Involves the alpha  Subunit of Eukaryotic Translation Initiation Factor 2 and NF-kappa B

Jesús Gil,1 José Alcamí,2 and Mariano Esteban1,*

Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Campus Universidad Autónoma, 28049 Madrid,1 and Centro de Investigación, Hospital 12 de Octubre, Carretera de Andalucía 5.400, 28041 Madrid,2 Spain

Received 28 December 1998/Returned for modification 5 February 1999/Accepted 25 March 1999

The double-stranded (ds) RNA-dependent protein kinase (PKR) is a key mediator of antiviral effects of interferon (IFN) and an active player in apoptosis induced by different stimuli. The translation initiation factor eIF-2alpha (alpha  subunit of eukaryotic translation initiation factor 2) and Ikappa Balpha , the inhibitor of the transcription factor NF-kappa B, have been proposed as downstream mediators of PKR effects. To evaluate the involvement of NF-kappa B and eIF-2alpha in the induction of apoptosis by PKR, we have used vaccinia virus (VV) recombinants that inducibly express PKR concomitantly with a dominant negative mutant of eIF-2alpha or a repressor form of Ikappa Balpha . We found that while expression of PKR by a VV vector resulted in extensive inhibition of protein synthesis and induction of apoptosis, coexpression of PKR with a dominant negative mutant of eIF-2alpha (Ser-51right-arrowAla) reversed both the PKR-mediated translational block and PKR-induced apoptosis. Coexpression of PKR with a repressor form of Ikappa Balpha (Ser-32,36-Ala) also leads to the inhibition of apoptosis by abolishing NF-kappa B induction, while translation remains blocked. Treating cells with two different proteasome inhibitors which block Ikappa Balpha degradation, prevented PKR-induced apoptosis, supporting results from coexpression studies. Biochemical analysis and transient assays revealed that PKR expression by a VV vector induced NF-kappa B binding and transactivation. In addition, upregulation of Fas mRNA transcription occurred during PKR activation. Our findings provide direct evidence for the involvement of eIF-2alpha and NF-kappa B in the induction of apoptosis by PKR.

* Corresponding author. Mailing address: Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma, 28049 Madrid, Spain. Phone: 34-91-585-4503. Fax: 34-91-585-4506. E-mail: mesteban{at}cnb.uam.es.

Molecular and Cellular Biology, July 1999, p. 4653-4663, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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