Phosphorylation of the NFAR proteins by the dsRNA-dependent protein kinase PKR constitutes a novel mechanism of translational regulation and cellular defense

Ai Harashima, Toumy Guettouche, Glen N. Barber

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Here, we describe a new mechanism of host defense that involves the nuclear factors associated with dsRNA (NFAR1 [90 kDa] and NFAR2 [110 kDa]), which constitute part of the shuttling ribonuclear protein (RNP) complex. Activation of the dsRNA-activated protein kinase PKR by viral RNA enabled phosphorylation of NFAR1 and NFAR2 on Thr 188 and Thr 315, an event found to be evolutionarily conserved in Xenopus. Phosphorylated NFAR1 and NFAR2 became dissociated from nuclear factor 45 (NF45), which was requisite for NFAR reshuttling, causing the NFARs to be retained on ribosomes, associate with viral transcripts, and impede viral replication. CreloxP animals with depletion of the NFARs in the thymus were exquisitely sensitive to the cytoplasmic replicating virus VSV (vesicular stomatitis virus). Thus, the NFARs constitute a novel, conserved mechanism of host defense used by the cell to detect and impede aberrant translation events.

Original languageEnglish (US)
Pages (from-to)2640-2653
Number of pages14
JournalGenes and Development
Volume24
Issue number23
DOIs
StatePublished - Dec 1 2010

Keywords

  • Host defense
  • mRNP export
  • NFAR
  • PKR
  • Translation

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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