Short double-stranded RNAs of specific sequence activate ribosomal TAK1-D and induce a global inhibition of translation.
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 beta-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.
Kodym
Reinhard
R
Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, 2201 Inwood Road, Dallas, TX 75390, USA. reinhard.kodym@utsouthwestern.edu
Kodym
Elisabeth
E
Story
Michael D
MD
D017209:Apoptosis; D045744:Cell Line, Tumor; D006801:Humans; D008168:Lung / Q000166:cytology; D020930:MAP Kinase Kinase Kinases / Q000032:analysis* / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000378:metabolism*; D054683:Ribosome Subunits, Large, Eukaryotic; D012270:Ribosomes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D020930:MAP Kinase Kinase Kinases; D012330:RNA, Double-Stranded; D000099151:MAP Kinase Kinase Kinase 7