• Citer

Translation inhibition in apoptosis: caspase-dependent PKR activation and eIF2-α phosphorylation

par Saelens, Xavier;Kalai, Michaël ;Vandenabeele, Peter
Référence The Journal of biological chemistry, 276, 45, page (41620-41628)
Publication Publié, 2001-11

Article révisé par les pairs

• Accès en ligne
• Détails
• Contenu
• Statistiques

Résumé :

The protein kinase PKR is a major player in the cellular antiviral response, acting mainly by phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (elF2-α) to block de novo protein synthesis. PKR activation requires binding of double-stranded RNA or PACT/RAX proteins to its regulatory domain. Since several reports have demonstrated that translation is inhibited in apoptosis, we investigated whether PKR and eIF2-α phosphorylation contribute to this process. We show that PKR is proteolysed and that eIF2-α is phosphorylated at the early stages of apoptosis induced by various stimuli. Both events coincide with the onset of caspase activity and are prevented by caspase inhibitors. Using site-directed mutagenesis we show that PKR is specifically proteolysed at Asp251 during cellular apoptosis. This site is cleaved in vitro by recombinant caspase-3, caspase-7, and caspase-8 and not by the proinflammatory caspase-1 and caspase-11. The released kinase domain efficiently phosphorylates eIF2-α at the cognate Ser51 residue, and its overexpression in mammalian cells impairs the translation of its own mRNA and of reporter mRNAs. Our results demonstrate a new and caspase-dependent activation mode for PKR, leading to eIF2-α phosphorylation and translation inhibition in apoptosis.