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The MAPK Hog1 recruits Rpd3 histone deacetylase to activate osmoresponsive genes

Abstract

Regulation of gene expression by mitogen-activated protein kinases (MAPKs) is essential for proper cell adaptation to extracellular stimuli. Exposure of yeast cells to high osmolarity results in rapid activation of the MAPK Hog1, which coordinates the transcriptional programme required for cell survival on osmostress1. The mechanisms by which Hog1 and MAPKs in general regulate gene expression are not completely understood, although Hog1 can modify some transcription factors2. Here we propose that Hog1 induces gene expression by a mechanism that involves recruiting a specific histone deacetylase complex to the promoters of genes regulated by osmostress. Cells lacking the Rpd3–Sin3 histone deacetylase complex are sensitive to high osmolarity and show compromised expression of osmostress genes. Hog1 interacts physically with Rpd3 in vivo and in vitro and, on stress, targets the deacetylase to specific osmostress-responsive genes. Binding of the Rpd3–Sin3 complex to specific promoters leads to histone deacetylation, entry of RNA polymerase II and induction of gene expression. Together, our data indicate that targeting of the Rpd3 histone deacetylase to osmoresponsive promoters by the MAPK Hog1 is required to induce gene expression on stress.

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Figure 1: Mutations in RPD3 and SIN3 render cells osmosensitive with impaired expression of osmostress genes.
Figure 2: Osmostress gene expression mediated by LexA–Hog1 is affected by deleting RPD3 and SIN3 or by modifying histone H4 lysines.
Figure 3: Hog1 physically interacts with Rpd3.
Figure 4: The Rpd3–Sin3 complex directly binds and deacetylates the HSP12 promoter to facilitate Pol II binding.

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Acknowledgements

We thank M. Carmona and D. Otero for technical assistance; J. Lozano for statistical treatment of the microarray data; and M. Beato, F. X. Real and G. Ammerer for advice. M.Z. is the recipient of a Ramón Areces Ph.D. fellowship and G.M. is the recipient of a Formación de Personal Universitario fellowship (MECD, Spanish government). E.d.N. and P.M.A. are supported by the Programa Ramón y Cajal. This work was supported by grants from the Ministerio de Ciencia y Tecnología, ‘Distinció de la Generalitat de Catalunya per a la Promoció de la Recerca Universitaria, Joves Investigadors’ DURSI (Generalitat de Catalunya), and the European Molecular Biology Organization YIP program to F.P.

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Correspondence to Francesc Posas.

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de Nadal, E., Zapater, M., Alepuz, P. et al. The MAPK Hog1 recruits Rpd3 histone deacetylase to activate osmoresponsive genes. Nature 427, 370–374 (2004). https://doi.org/10.1038/nature02258

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