Abstract
Accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) causes ER stress. Snf1, the Saccharomyces cerevisiae ortholog of AMP–activated protein kinase (AMPK), plays a crucial role in the response to various environmental stresses. However, the role of Snf1 in ER stress response remains poorly understood. In this study, we characterize Snf1 as a negative regulator of Hog1 MAPK in ER stress response. The snf1 mutant cells showed the ER stress resistant phenotype. In contrast, Snf1-hyperactivated cells were sensitive to ER stress. Activated Hog1 levels were increased by snf1 mutation, although Snf1 hyperactivation interfered with Hog1 activation. Ssk1, a specific activator of MAPKKK functioning upstream of Hog1, was induced by ER stress, and its induction was inhibited in a manner dependent on Snf1 activity. Furthermore, we show that the SSK1 promoter is important not only for Snf1-modulated regulation of Ssk1 expression, but also for Ssk1 function in conferring ER stress tolerance. Our data suggest that Snf1 downregulates ER stress response signal mediated by Hog1 through negatively regulating expression of its specific activator Ssk1 at the transcriptional level. We also find that snf1 mutation upregulates the unfolded protein response (UPR) pathway, whereas Snf1 hyperactivation downregulates the UPR activity. Thus, Snf1 plays pleiotropic roles in ER stress response by negatively regulating the Hog1 MAPK pathway and the UPR pathway.
Highlights
The endoplasmic reticulum (ER) is the cellular organelle responsible for the folding and modification of newly synthesized secretory or membrane proteins
Numerous studies have shown that a family of protein kinases plays a principal role in adaptive response to environmental stresses and perturbation of their regulation is implicated in a variety of human pathologies, such as cancer and neurodegenerative diseases
We demonstrate that a Saccharomyces cerevisiae ortholog of mammalian AMP–activated protein kinase (AMPK), Snf1, negatively regulates Hog1 in ER stress response
Summary
The endoplasmic reticulum (ER) is the cellular organelle responsible for the folding and modification of newly synthesized secretory or membrane proteins. Environmental or developmental changes which perturb ER homeostasis, or genetic alterations causing production of irreversibly misfolded proteins lead to an accumulation of unfolded and misfolded proteins within the ER This condition, which is collectively termed ER stress, is toxic to cells and has been implicated in a variety of human pathologies, such as diabetes, cancer and neurodegeneration, including Alzheimer, Parkinson and Huntington disease [1, 2]. The UPR is undoubtedly essential for yeast cells to alleviate ER stress, a previous genome-wide study [4] has predicted that not less than 100 genes are involved in response to ER stress. It remains to be fully elucidated how ER stress response is precisely controlled
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