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Cellular signalling systems

Proper regulation of the phenotype requires cells to possess a method of interrogating the external environment and responding in an appropriate manner. This is accomplished by the use of arrays of sensors capable of detecting the nutritional and stress status of the environment, coupled to pathways through which signals are transmitted to targets that adjust metabolism to elicit an appropriate response. The relative simplicity of using S. cerevisiae as a model cell has made it a favourite for studying this subject and a great deal is now known, albeit much less in the case of brewing strains. Conrad et al. (2014) have published an excellent review summarizing current knowledge.

Several signalling systems are recognized and they share in common the ability of cells to sense the concentrations of relatively simple nutrients, and to generate multiple responses. The latter is obvious since, for example, starvation ofan essential nutrient must not only switch off pathways necessary for growth and proliferation but must also re-engineer metabolism so that the cell acquires a resistant phenotype. Conversely, when conditions become growth-promoting these changes must be reversible. Responses to external cues must be sufficiently rapid to allow timely metabolic shifts and this suggests that many of the changes are likely to involve post-translational modifications. Different levels of control are exquisitely poised to elicit an appropriate response.

Signalling pathways identified in yeast include those for glucose repression and concomitant fermentative metabolism, nitrogen catabolite repression, general amino acid control, phosphate regulation, and regulatory responses triggered by sulfate, metal ions, and some vitamins. Signalling pathways may be implicated in the regulation of uptake of a single or small related class of nutrients; alternatively, general nutrient signalling systems are responsive to the concentrations of multiple classes of nutrients that elicit more global shifts, such as control of biomass formation, progression through the cell cycle, acquisition of stress tolerance, accumulation or mobilization of storage reserves, and apoptosis. Conrad et al. (2014) provide the illuminating example that starvation of both zinc and iron will individually trigger the induction of their respective high-affinity uptake systems but with no cross-talk. However, starvation of both ions also elicits a common general response in which growth arrests and there is an increase in stress tolerance. Receptors that are specific to a single or small group of molecules and cause induction of separate specific uptake systems may have themselves, in an earlier evolutionary phase, functioned as transporters, although they have now lost this function (Ozcan et al., 1996).

In order to exert their effects, it is suggested that the triggering nutrients require some degree of metabolic processing. This is consistent with the observation that, for example, the ability of exogenous glucose to cause transition from quiescence requires metabolism at least to pyruvate (McKnight, 2010). The general responses require a target capable of responding to multiple nutrients. Responses may be long or short term and involve different mechanisms. This would be expected to allow for both rapid adjustment of the carbon flux through specific pathways to allow cells to make selective advantage of sudden changes in the environment, and slower global changes such as passage into and out of quiescence. The longer-term responses appear to be via regulation of the genotype, notably by nutrients of ribosomal protein gene expression (Griffioen et al., 1996). The more rapid responses are mediated by cascades of phosphorylation, involving reactions between target enzymes and kinases and phosphatases with regulatory functions. It has been reported that, of 204 enzymes involved in central carbon and amino-acid metabolism, some 35 were observed to change their degree of phosphorylation under five different growth conditions (Oliveira et al., 2012; Oliveira and Sauer, 2012). Signals are transmitted in reactions in which, for example, starvation of several individual nutrients interact reversibly with a common target kinase, and in response the activities of multiple pathways are modulated by the targets of the kinase. In S. cerevisiae, some 120 kinases and 40 phosphatases have been identified (Bodenmiller et al., 2010). The effect of phosphorylation on the target protein can result in inactivation or activation by conformational changes, access to the catalytic site, tagging for degradation, intra-organelle translocation, and facilitating association or disassociation with multiprotein complexes (Oliveira et al., 2012).

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