Dataset Information

Thiol-Based Direct Threat Sensing by the Stress-Activated Protein Kinase Hog1

ABSTRACT: The stress-activated protein kinase Hog1 is best known for its role in osmotic stress but is also activated by a variety of mechanistically distinct environmental stressors including heat shock, ER stress, and arsenic. In the osmotic stress response, the signal is sensed upstream and relayed to Hog1 via a kinase cascade. Here we identify a novel mode of Hog1 function whereby Hog1 senses arsenic though direct physical interaction requiring three conserved cysteine residues located adjacent to the catalytic loop. These residues are essential for Hog1's role in protecting against arsenic, but completely dispensable for osmotic stress, and mediate Hog1's cellular localization upon arsenic exposure. Hog1 in turn regulates arsenic detoxification by phosphorylating the transcription factor Yap8, promoting its nuclear localization, and stimulating transcription of its only known targets, Arr2 and Arr3, which promote arsenic efflux. Arsenic binding was also observed with the related human kinases Erk1 and Erk2, suggesting that this may be a conserved aspect of this kinase family. These data provide a mechanistic basis for understanding how stress-activated kinases can sense individual threats and carry out highly specific adaptive responses.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

TISSUE(S): Cell Suspension Culture

SUBMITTER: Miguel Prado

LAB HEAD: Daniel Finley

PROVIDER: PXD015325 | Pride | 2019-12-04

REPOSITORIES: Pride

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Thiol-based direct threat sensing by the stress-activated protein kinase Hog1.

Guerra-Moreno Angel A Prado Miguel A MA Ang Jessie J Schnell Helena M HM Micoogullari Yagmur Y Paulo Joao A JA Finley Daniel D Gygi Steven P SP Hanna John J

Science signaling 20191126 609

The yeast stress-activated protein kinase Hog1 is best known for its role in mediating the response to osmotic stress, but it is also activated by various mechanistically distinct environmental stressors, including heat shock, endoplasmic reticulum stress, and arsenic. In the osmotic stress response, the signal is sensed upstream and relayed to Hog1 through a kinase cascade. Here, we identified a mode of Hog1 function whereby Hog1 senses arsenic through a direct physical interaction that require ...[more]

PMID: 31772124

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Project description:Epigenetic information is able to interact with the cellular environment and therefore it could be especially useful for reprogramming gene expression in response to a physiological perturbation. In fact, genes induced or repressed by osmotic stress undergo significant changes in the levels of various histone modifications, especially the acetylation levels of histone H3. Exposure of yeast to high osmolarity results in the activation of p38-related SAPK, Hog1, which plays a central role in the control of gene expression. Therefore, two types of mechanisms converge in gene regulation by stress: that of the epigenetic signals and that of the trans-acting protein factor. We have evaluated the connection between the presence of Hog1 and the changes on acetylation of histone H3 in stress-regulated genes. Furthermore, we asked which enzymatic activities are involved in the changes produced in the acetylation of H3 linked to gene activation by osmotic stress. We have demonstrated that increase of acetylation of lysines 9 and 14 of H3 produced on induced genes during stress positively correlates between them and are largely dependent on Hog1 at genome-wide level. Conversely, decrease in acetylation on repressed genes was not dependent on Hog1. However, the absence of Hog1 produces different and even opposite effects on the induction and acetylation of H3 of each gene, which suggests that Hog1 influences both processes through different mechanisms. Additionally, we found that in genes up-regulated during osmotic stress in a Msn2/Msn4-independent manner, the state of acetylation of lysine 9 of H3 was altered in strains deficient in Nut1 HAT and Hos1 HDAC; meanwhile for Msn2/Msn4-dependent induced genes H3k9 acetylation varies in strains deficient in Sas2 HAT and Rpd3 HDAC. During induction by osmotic stress at least two different mechanism act on H3k9 acetylation of two differentiated set of induced genes, one of them would act through Nut1/Hos1, while the other through Sas2/Rpd3. The results presented here show new and unexpected participants in the process of the regulation of gene in response to environmental perturbations.

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