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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

SCImago Journal Rank (SJR) 2015: 1.607
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Impact per Publication (IPP) 2015: 2.609

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

Reinhard Kodym1 / Elisabeth Kodym1 / Michael D. Story1

1Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, 2201 Inwood Road, Dallas, TX 75390, USA

Corresponding author

Citation Information: Biological Chemistry. Volume 390, Issue 5/6, Pages 453–462, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/BC.2009.046, March 2009

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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.

Keywords: apoptosis; dsRNA; protein translation; ribosome; ribotoxic stress

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