COLMAN LERNER Alejandro Ariel
Single-cell profiling screen identifies microtubule-dependent reduction of variability in cell signaling
GUSTAVO PESCE; STEFAN ZDRALJEVIC; WILLIAM PERIA; ALAN BUSH; VICTORIA REPETTO; DAN ROCKWELL; RICHARD YU; ALEJANDRO COLMAN LERNER; ROGER BRENT
MOLECULAR SYSTEMS BIOLOGY
NATURE PUBLISHING GROUP
Lugar: Londres; Año: 2018 vol. 14 p. 1 - 20
Populations of isogenic cells often respond coherently to signals, despite differences in protein abundance and cell state. Previously, we uncovered processes in the Saccharomyces cerevisiae pheromone response system (PRS) that reduced cell-to-cell variability in signal strength and cellular response. Here, we screened 1141 nonessential genes to identify 50 "variability genes". Most had distinct, separable effects on strength and variability of the PRS, defining these quantities as genetically distinct ?axes? of system behavior. Three genes affected cytoplasmic microtubule function: BIM1, GIM2 and GIM4. We used genetic and chemical perturbations to show that, without microtubules, PRS output is reduced but variability is unaffected, while, when microtubules are present but their function is perturbed, output is sometimes lowered, but its variability is always high. The increased variability caused by microtubule perturbations required the PRS MAP kinase Fus3 and a process at or upstream of Ste5, the membrane-localized scaffold to which Fus3 must bind to be activated. Visualization of Ste5 localization dynamics demonstrated that perturbing microtubules destabilized Ste5 at the membrane signaling site. The fact that microtubule perturbations cause aberrant fate and polarity decisions in mammals suggests that microtubule-dependent signal stabilization might operate in metazoans.