The SMuSh pathway is essential for survival during growth-induced compressive mechanical stress

Abstract

Cells that proliferate within a confined environment build up mechanical compressive stress. For example, mechanical pressure emerges in the naturally space-limited tumor environment. However, little is known about how cells sense and respond to mechanical compression. We developed microfluidic bioreactors to enable the investigation of the effects of compressive stress on the growth of the genetically tractable model organism Saccharomyces cerevisiae. We used this system to determine that compressive stress is partly partly sensed through a module consisting of the mucin Msb2, and the cell wall protein Sho1, which act together as a sensor module in one of the two major osmosensing pathways in budding yeast. This signal is transmitted via the MAPKKK kinase Ste11. Thus, we term this mechanosensitive pathway the SMuSh pathway, for Ste11 through Mucin / Sho1 pathway. The SMuSh pathway delays cells in the G1 phase of the cell cycle and improves cell survival in response to growth-induced pressure. We also found that the Cell Wall Integrity (CWI) pathway contributes to the response to mechanical compressive stress. These latter results are confirmed in complimentary experiments in the accompanying manuscript from Mishra et al. When both the SMuSh and the CWI pathways are deleted, cells fail to adapt to compressive stress and all cells lyse at relatively low pressure when grown in confinement. Thus, we define a network that is essential for cell survival during growth under pressure. We term this new mechanosensory system the SCWISh (Survival through the CWI and SMuSh) network.\n\nSignificance StatementGrowth in confined environments leads to the build up of compressive mechanical stresses, which are relevant to diverse fields, from cancer to microbiology. In contrast to tensile stress, little is known about the molecular integration of compressive stresses. In this study, we elucidate the SMuSh pathway, which, together with the Cell Wall Integrity pathway, is essential for viability of the budding yeast S. cerevisiae when growing under mechanical pressure. Pressure-sensing requires the transmembrane mucin, Msb2, which is linked to the actin cortex. Our result raises the intriguing question of whether mucins, widely conserved in eukaryotes and frequently misregulated in cancers, might sense compressive stresses in other organisms, including humans.