## 2 Osmoadaptation Mechanisms in Yeast  
Numerous studies conducted in the yeast _S. cerevisiae_ have contributed to the understanding of the high osmolarity glycerol (HOG) pathway (reviewed in [1]). Activation of the HOG pathway depends on an increase in osmotic pressure resulting in a change in the expression of several genes. The molecular response to osmotic stress in _S. cerevisiae_ is mediated by mitogen-activated protein kinase (MAPK) signaling pathways. Hog1p MAPK plays a central role in this signaling system, where Hog1p is activated by a two-component His-to-Asp phosphorelay system that includes Sln1p, a histidine kinase sensor; Ypd1p, a histidine-containing phosphotransfer protein; and Ssk1p and Skn7p response regulators [15,16] (Figure 1). Sln1p protein consists of an extracellular sensor, a kinase and a response regulator domain, giving a transmembrane hybrid-type histidine kinase. Under low-osmolarity, a specific histidine residue (His576) within the histidine kinase domain is autophosphorylated. Then, the phosphate group of the histidine kinase domain is transferred to an aspartate residue (Asp1144) within the receiver domain of Sln1p. Through a His-Asp phosphorelay, the phosphate group is transferred to the downstream Ypd1p phosphotransmitter, and then to the Ssk1p response regulator [12,15,17]. Phosphorylated Ssk1p fail to interact with the redundant pair of MAPKKK Ssk2p/Ssk22p, resulting in an inactive Ssk2p/Ssk22p-Pbs2p (MAPK)-Hog1p form [18]. However, when yeast are exposed to osmotic stress, Sln1p is inhibited resulting in dephosphorylated forms of Ypd1p and Ssk1p, leading to Ssk1p-Ssk2p/Ssk22p interactions and finally the activation of Hog1p by phosphorylation [18]. In hyperosmotic environments, activated Hog1p migrates to the nucleus. This action is mediated by Gsp1p, a small GTP-binding protein, and the importin homologue Nmd5p; and it is independent of the NLS-binding importin/heterodimer [19]. Activation of the HOG pathway leads to the induction of genes required for osmotic stress response, for example glycerol biosynthesis genes such as the genes encoding a glycerol-3-phosphate dehydrogenase (GPD1) and glycerol-3-phosphatase (GPP2) [20,21]. A nuclear exchange sequence receptor protein called Crm1p exports dephosphorylated Hog1p back to the cytoplasm [19]. Negative regulation of Hog1p is exerted through phosphotyrosine phosphatases, Ptp2p and Ptp3p, in both the nucleus and the cytoplasm, respectively [22]; and the phosphatase Ptc1p, Ptc2p and Ptc3p [23,24]. Ptc1p dephosphorylates Hog1p _via_ a docking interaction between Ptc1p, Hog1p, and Pbs2p joining a small adaptor named Nbp2p [25,26]. In addition, in yeast Hog1p is regulated by a second mechanism, which includes a transmembrane sensor kinase called Sho1p (Figure 1). In the Sho1 branch, a multi-component signaling complex consisting of Sho1p, Cdc42p, Ste20p/Cla4p, Ste50p, Ste11p (MAPKKK), Pbs2p is formed in hyperosmotic environments. Pbs2p is localized to the membrane by its proline-based motif and an SH3 domain on Sho1. Pbs2p binds the MAPKKK Ste11p which is phosphorylated by the PAK-like kinase Ste20p, which is itself recruited to the membrane by activated Cdc42. Activated Ste11p then phosphorylates Pbs2p which in turn activates the downstream Hog pathway [26,27]. Hkr1p and Msb2p, mucin-like transmembrane proteins [27], are potential sensors for the Sho1p mechanism that activates Hog1p when the yeast is exposed to osmotic stress. Activation of Hog1p can also lead to phosphorylation of the Sko1p bZip-type repressor, which results in the disassembly of Sko1p-Tup1p-Ssn6p repressor complexes [28]. Phosphorylated Hog1p interacts with the RCS chromatin-remodeling complex to mediate its recruitment to osmo-responsive genes [29]. Hog1p also recruits the Rpd3p histone deacetylase to osmoresponsive gene promoters inducing their expression during osmotic stress [30].