Serine 18 phosphorylation of RAX, the PKR activator, is required for PKR activation and consequent translation inhibition

Richard L. Bennett, William L. Blalock, W. Stratford May

Research output: Contribution to journalArticlepeer-review

Abstract

It is now apparent that the double-stranded (ds)RNA-dependent protein kinase, PKR, is a regulator of diverse cellular responses to stress. Recently, the murine dsRNA-binding protein RAX and its human ortholog PACT were identified as cellular activators of PKR. Previous reports demonstrate that following stress, RAX/PACT associates with and activates PKR resulting in eIF2α phosphorylation, consequent translation inhibition, and cell death via apoptosis. Although RAX/PACT is phosphorylated during stress, any regulatory role for this post-translational modification has been uncertain. Now we have discovered that RAX is phosphorylated on serine 18 in both human and mouse cells. The non-phosphorylatable form of RAX, RAX(S18A), although still able to bind dsRNA and associate with PKR, fails to activate PKR following stress. Furthermore, stable expression of RAX(S18A) results in a dominant-negative effect characterized by deficiency of eukaryotic initiation factor 2 α subunit phosphorylation, delay of translation inhibition, and failure to undergo rapid apoptosis following removal of interleukin-3. We propose that the ability of RAX to activate PKR is regulated by a sequential mechanism featuring RAX association with PKR, RAX phosphorylation at serine 18, and activation of PKR.

Original languageEnglish
Pages (from-to)42687-42693
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number41
DOIs
Publication statusPublished - Oct 8 2004

ASJC Scopus subject areas

  • Biochemistry

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