Controlled protein super-assembly allows confinement of cellular memory to the yeast mother cell

Orateur : Fabrice CAUDRON (labo Yves Barral, ETH, Zürich)

Cells have to adapt constantly to their fluctuating environment and neighbors in order to survive. Adaptations can be stored as memories and recent evidences point towards the widespread existence of cellular memories. We have discovered a new type of epigenetic memory that allows a budding yeast cell to ignore a pheromone mediated mating signal after unproductive exposure to this pheromone. This memory relies on the conformational change and consequent inactivation of the Whi3 mnemon, a protein involved in the inhibition of cell cycle entry. Interestingly, this pheromone refractory state stays in the mother cell and does not spread to daughter cells. I will describe our efforts aimed at understanding what triggers Whi3 super-assembly in the context of pheromone response. We identified the mitogen activated protein kinase Kss1 as critical for Whi3 super-assembly. Furthermore, I will present evidences that a lateral membrane diffusion barrier in the endoplasmic reticulum confines the Whi3 mnemon and the pheromone refractory state in the mother cell. The link between the ER membrane and Whi3 super-assemblies involves the protein complex composed of the Far3 and Far7 to Far11 proteins. When either the diffusion barrier or the Far complex are non-functional, daughter cells are more likely born with a refractory state to pheromone. More importantly, loss of mnemon confinement led to its transformation into a prion at high frequency. In the prion state, the refraction to pheromone spread to daughter cells and the whole progeny. Indeed, in diffusion barrier mutants, some cells could divide and form colonies even in the presence of high pheromone concentration. This phenotype revealed a complex cellular protein aggregation landscape. Therefore, we propose that confinement of protein conformational changes in the context of adaptive behavior and memory is critical for the control of protein aggregation and cellular physiology.

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