Protein kinase Snf1 is involved in the proper regulation of the unfolded protein response in Saccharomyces cerevisiae.
Glc7 is the only catalytic subunit of the protein phosphatase type 1 in the yeast S. cerevisiae and, together with its regulatory subunits, is involved in many essential processes. Analysis of the non-essential mutants in the regulatory subunits of Glc7 revealed that the lack of Reg1, and no other subunit, causes hypersensitivity to unfolded protein response (UPR)-inducers, which was concomitant with an augmented UPR element-dependent transcriptional response. The Glc7-Reg1 complex takes part in the regulation of the yeast AMP-activated serine/threonine protein kinase Snf1 in response to glucose. We demonstrate in the present study that the observed phenotypes of reg1 mutant cells are attributable to the inappropriate activation of Snf1. Indeed, growth in the presence of limited concentrations of glucose, where Snf1 is active, or expression of active forms of Snf1 in a wild-type strain increased the sensitivity to the UPR-inducer tunicamycin. Furthermore, reg1 mutant cells showed a sustained HAC1 mRNA splicing and KAR2 mRNA levels during the recovery phase of the UPR, and dysregulation of the Ire1-oligomeric equilibrium. Finally, overexpression of protein phosphatases Ptc2 and Ptc3 alleviated the growth defect of reg1 cells under endoplasmic reticulum (ER) stress conditions. Altogether, our results reveal that Snf1 plays an important role in the attenuation of the UPR, as well as identifying the protein kinase and its effectors as possible pharmacological targets for human diseases that are associated with insufficient UPR activation.
*Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain.
Jofre
J
Ferrer-Dalmau
†Departamento de Biotecnología, Instituto de Agroquímica y Tecnología de los Alimentos, Consejo Superior de Investigaciones Científicas, 46980 Paterna, Valencia, Spain.
Francisca
F
Randez-Gil
*Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain.
Maribel
M
Marquina
†Departamento de Biotecnología, Instituto de Agroquímica y Tecnología de los Alimentos, Consejo Superior de Investigaciones Científicas, 46980 Paterna, Valencia, Spain.
José A
JA
Prieto
*Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain.
Antonio
A
Casamayor
D020134:Catalytic Domain / Q000235:genetics; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D054645:Protein Phosphatase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing; D012331:RNA, Fungal / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics
D008562:Membrane Glycoproteins; D012331:RNA, Fungal; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; D014415:Tunicamycin; C071570:SNF1-related protein kinases; C082863:IRE1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C092048:GLC7 protein, S cerevisiae; C491716:PTC2 protein, S cerevisiae; C000607464:PTC3 protein, S cerevisiae; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D000071636:Protein Phosphatase 2C; C070829:REG1 protein, S cerevisiae