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Molecular and Cellular Biology, May 2004, p. 4502-4512, Vol. 24, No. 10
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.10.4502-4512.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

TRAF Family Proteins Link PKR with NF-{kappa}B Activation

Jesús Gil ,1,{dagger},{ddagger} Maria Angel García,1,{dagger} Paulino Gomez-Puertas,2 Susana Guerra,1 Joaquín Rullas,3 Hiroyasu Nakano,4 José Alcamí,3 and Mariano Esteban1*

Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Campus Universidad Autónoma, 28049 Madrid,1 Bioinformatics Laboratory, Centro de Astrobiología, CAB-CSIC, Torrejón de Ardoz, 28850 Madrid,2 Laboratorio de Inmunopatología del SIDA, Centro de Biología Fundamental, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain,3 Department of Immunology, School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan4

Received 15 September 2003/ Returned for modification 16 October 2003/ Accepted 20 February 2004

The double-stranded RNA (dsRNA)-dependent protein kinase PKR activates NF-{kappa}B via the I{kappa}B kinase (IKK) complex, but little is known about additional molecules that may be involved in this pathway. Analysis of the PKR sequence enabled us to identify two putative TRAF-interacting motifs. The viability of such an interaction was further suggested by computer modeling. Here, we present evidence of the colocalization and physical interaction between PKR and TRAF family proteins in vivo, as shown by immunoprecipitation and confocal microscopy experiments. This interaction is induced upon PKR dimerization. Most importantly, we show that the binding between PKR and TRAFs is functionally relevant, as observed by the absence of NF-{kappa}B activity upon PKR expression in cells genetically deficient in TRAF2 and TRAF5 or after expression of TRAF dominant negative molecules. On the basis of sequence information and mutational and computer docking analyses, we favored a TRAF-PKR interaction model in which the C-terminal domain of TRAF binds to a predicted TRAF interaction motif present in the PKR kinase domain. Altogether, our data suggest that TRAF family proteins are key components located downstream of PKR that have an important role in mediating activation of NF-{kappa}B by the dsRNA-dependent protein kinase.

* Corresponding author. Mailing address: Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma, 28049 Madrid, Spain. Phone: 34-91-585-4553. Fax: 34-91-585-4506. E-mail: mesteban{at}cnb.uam.es.

{dagger} J.G. and M.A.G. contributed equally to this work.

{ddagger} Present address: Molecular Oncology Laboratory, Cancer Research UK, London Research Institute, London WC2A 3PX, United Kingdom.

Molecular and Cellular Biology, May 2004, p. 4502-4512, Vol. 24, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.10.4502-4512.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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