Protein kinase Snf1 is involved in the proper regulation of the unfolded protein response in Saccharomyces cerevisiae

Abstract

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.

The Saccharomyces cerevisiae AMPK, Snf1, Negatively Regulates the Hog1 MAPK Pathway in ER Stress Response

“…It is possible that Snf1 coordinates ER stress response with other cellular responses, since Snf1 is activated in the response to various environmental stresses [ 5 , 6 , 15 ]. Indeed, it has been reported that ER stress sensitivity is enhanced under the extracellular environments in which Snf1 activity is known to be elevated [ 28 ]. Alternatively, Snf1 may function to inactivate Hog1 in the whole cell level.…”

“…Therefore, the mechanisms by which the UPR is finally attenuated have yet to be elucidated. In the course of preparation of this manuscript, Casamayor and colleagues also reported that Snf1 is involved in yeast ER stress response [ 28 ]. Consistent with our findings, they showed that reg1 mutation results in increased sensitivity to ER stress in a Snf1-dependent manner.…”

Expression control of the AMPK regulatory subunit and its functional significance in yeast ER stress response

“…Previous studies from us and another group demonstrated the involvement of Snf1 in ER stress response1819. We have revealed Snf1 as a negative regulator of the UPR pathway and the Hog1 MAPK pathway in ER stress response19.…”

Induction of Ptp2 and Cmp2 protein phosphatases is crucial for the adaptive response to ER stress in Saccharomyces cerevisiae

“…Nevertheless, why do yeast cells possess the mechanism by which Hog1 is negatively regulated through Ptp2 induction in response to ER stress? Previous studies suggested that ER stress sensitivity of the budding yeast is altered by the extracellular environments, including the composition of the culture medium 8 , 41 . Furthermore, it is well-known that the activity of Hog1 and Mpk1 are dynamically modulated by various environmental conditions 42 , 43 .…”