The Msn2 Way: Intricacies of the Stress Response in Budding Yeast

Abstract

S. cerevisiae are able to sense and adapt to changing environmental conditions, including nutrient availability, osmolarity, and temperature. The general stress response pathway helps shield yeast cells from unfavorable environments and anticipated hardships. This pathway involves the Msn2 transcription factor which, upon a stress, enters the nucleus and promotes transcription of diverse stress response genes. Because Msn2 is a node at which many signaling pathways converge, it is a useful model for understanding how a cell integrates information from multiple and possibly conflicting inputs. We have used single-cell analysis of Msn2-GFP containing strains to monitor nuclear localization in response to single and multiple stresses. We find that some stresses result in a resonance pattern of Msn2 shuttling in and out of the nucleus and that these oscillations vary in number and in magnitude from cell to cell within a genetically identical culture, pointing to a stochastic noise component built into the signaling circuit. Combining genetics and microscopy, we have sufficiently dissected the signaling events for glucose deprivation to identify PKA, Snf1, and PP1 as the triumvirate of the glucose response and to enable us to build a biochemical model that offers insights into signaling mechanics in general. Moreover, we find that these components serve as the primary vectors for regulating Msn2 localization, not only in response to glucose depletion but also to increased osmolarity and nitrogen deprivation. We discuss these observations in the context of coherent transcriptional activation of the cohort of stress responsive genes and in the role of stochastic noise in providing identical cells a diversity of responses to a common signal, providing cells with the ability to "hedge their bets" regarding future events.