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Abstract
Activated dsRNA-dependent serine/threonine kinase PKR phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2α), resulting in a shut-off of general translation, induction of apoptosis, and inhibition of virus replication. PKR can be activated by binding to dsRNA or cellular proteins such as PACT/RAX, or by its conjugation to ISG15 or SUMO. Here, we demonstrate that PKR also interacts with SUMO in a non-covalent manner. We identify the phosphorylable tyrosine residue 162 in PKR (Y162) as a modulator of the PKR-SUMO non-covalent interaction as well as of the PKR SUMOylation. Finally, we show that the efficient SUMO-mediated eIF2α phosphorylation and inhibition of protein synthesis induced by PKR in response to dsRNA depend on this residue. In summary, our data identify a new mechanism of regulation of PKR activity and reinforce the relevance of both, tyrosine phosphorylation and SUMO interaction in controlling the activity of PKR.
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Details
1 Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología-CSIC, Darwin 3, Madrid, Spain; Department of Molecular Genetics, University of Toronto, 1 Kings College Circle, Toronto, Canada
2 Centro de Investigación en Medicina Molecular (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain
3 Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Santiago de Compostela, Spain
4 Departamento de Fisioloxía and Centro de Investigación en Medicina Molecular (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain
5 Advanced Technology Institute in Life Sciences (ITAV) CNRS-USR3505, 31106, Université de Toulouse, UPS, Toulouse, France; Institut de Pharmacologie et de Biologie Structurale (IPBS) CNRS-UMR5089, 31077, Université de Toulouse, UPS, Toulouse, France
6 Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología-CSIC, Darwin 3, Madrid, Spain
7 Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología-CSIC, Darwin 3, Madrid, Spain; Centro de Investigación en Medicina Molecular (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain