EC Accepts, published online ahead of print on 30 October 2009

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Eukaryotic Cell doi:10.1128/EC.00185-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The Role of the Mitogen-activated Protein Kinase Sty1 in Regulation of eIF2 Kinases in Response to Environmental Stress in Schizosaccharomyces pombe

Juan José Berlanga, Damariz Rivero, Ruth Martín, Saturnino Herrero, Sergio Moreno, and César de Haro^*

Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Cantoblanco, Madrid, Spain; Department of Pharmacology, University of Florence, Florence, Italy; Institute of Applied Biosciences, Department of Applied Microbiology, University of Karlsruhe, Germany; and Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Salamanca, Spain

^* To whom correspondence should be addressed. Email: cdeharo{at}cbm.uam.es.

The mitogen-activated protein kinase (MAPK) Sty1 is essential for the regulation of transcriptional responses that promote cell survival in response to different types of environmental stimuli in Schizosaccharomyces pombe. In fission yeast, three distinct eukaryotic initiation factor 2 (eIF2) kinases, two mammalian HRI-related protein kinases (Hri1 and Hri2) and the Gcn2 ortholog, regulate protein synthesis in response to cellular stress conditions. In this study, we demonstrate that both Hri1 and Hri2 exhibited an autokinase activity, specifically phosphorylated eIF2, and functionally replaced the endogenous Saccharomyces cerevisiae Gcn2. We further show that Gcn2, but not Hri1 or Hri2, is activated early after exposure to hydrogen peroxide and methyl methanesulfonate (MMS). Cells lacking Gcn2 exhibit a later activation of Hri2. The activated MAPK Sty1 negatively regulates Gcn2 and Hri2 activities under oxidative stress, but not in response to MMS. By contrast, Hri2 is the primary activated eIF2 kinase in response to heat shock. In this case, the activation of Sty1 appears to be transitory and does not contribute to the modulation of the eIF2 kinase stress pathway. In strains lacking Hri2, a type 2A protein phosphatase is activated soon after heat shock to reduce eIF2 phosphorylation. Finally, the MAPK Sty1, but not the eIF2 kinases, is essential for survival upon oxidative stress or heat shock, but not upon MMS treatment. These findings point to a regulatory coordination between the Sty1 MAP kinase and eIF2 kinase pathways for a particular range of stress responses.