Role of mitogen-activated protein kinase Sty1 in regulation of eukaryotic initiation factor 2alpha kinases in response to environmental stress in Schizosaccharomyces pombe.
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 2alpha (eIF2alpha) 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 eIF2alpha, 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. In contrast, Hri2 is the primary activated eIF2alpha 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 eIF2alpha kinase stress pathway. In strains lacking Hri2, a type 2A protein phosphatase is activated soon after heat shock to reduce eIF2alpha phosphorylation. Finally, the MAPK Sty1, but not the eIF2alpha 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 MAPK and eIF2alpha kinase pathways for a particular range of stress responses.
Berlanga
Juan José
JJ
Centro de Biología Molecular Severo Ochoa, CSIC-UAM, 28049 Madrid, Spain.
Rivero
Damariz
D
Martín
Ruth
R
Herrero
Saturnino
S
Moreno
Sergio
S
de Haro
César
C
D000818:Animals; D002470:Cell Survival; D015971:Gene Expression Regulation, Enzymologic; D015966:Gene Expression Regulation, Fungal; D018869:Heat-Shock Response / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009153:Mutagens / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D012568:Schizosaccharomyces / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
D009153:Mutagens; D016877:Oxidants; D029701:Saccharomyces cerevisiae Proteins; D029702:Schizosaccharomyces pombe Proteins; D008741:Methyl Methanesulfonate; D006861:Hydrogen Peroxide; C512912:GCN2 protein, S cerevisiae; C466820:Hri1p protein, S pombe; C466819:Hri2p protein, S pombe; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D020928:Mitogen-Activated Protein Kinases; C095409:sty1 protein, S pombe