Short double-stranded RNAs of specific sequence activate ribosomal TAK1-D and induce a global inhibition of translation

Reinhard Kodym, Elisabeth Kodym, Michael D. Story

Research output: Contribution to journalArticle

Abstract

We have previously shown that short double-stranded RNAs of specific sequence induce phosphorylation in the activation loop of splicing variant D of the transforming growth factor β-activated protein kinase 1 (TAK1-D). Here, we further characterize this novel function of TAK1-D and the mechanisms of this dsRNA-triggered phenomenon. Using a dominant negative TAK1-D mutant we demonstrate that TAK1-D activation is functionally required to trigger the activation of p38 MAP kinase and c-JUN terminal kinase and to induce cell death in NCI-H460 cells. While total TAK1-D protein was found in the cytoplasm as well as in the ribosomal fraction, activated TAK1-D phosphorylated on T184 and T187 in the activation loop was found to be exclusively associated with the 80S ribosome. The association of TAK1-D with the ribosome suggests an involvement in translation-dependent signaling and we demonstrate here that dsRNA-mediated activation of TAK1-D leads to a downregulation of mRNA translation. In addition, we show that TAK1-D is also phosphorylated after the induction of ribotoxic stress. Our data indicate that TAK1-D plays a role in the signaling events triggered by selected types of ribotoxic stress.

Original languageEnglish (US)
Pages (from-to)453-462
Number of pages10
JournalBiological Chemistry
Volume390
Issue number5-6
DOIs
StatePublished - May 1 2009

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Keywords

  • Apoptosis
  • DsRNA
  • Protein translation
  • Ribosome
  • Ribotoxic stress

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Clinical Biochemistry

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