Cells need to organise and regulate their biochemical processes both in space and time in order to adapt to their surrounding environment. Spatial organisation of cellular components is facilitated by a complex network of membrane bound organelles. Both the membrane composition and the intra-organellar content of these organelles can be specifically and temporally controlled by imposing gates, much like bouncers controlling entry into night-clubs. In addition, a new level of compartmentalisation has recently emerged as a fundamental principle of cellular organisation, the formation of membrane-less organelles. Many of these structures are dynamic, rapidly condensing or dissolving and are therefore ideally suited to be involved in emergency cellular adaptation to stresses. Remarkably, the same proteins have also the propensity to adopt self-perpetuating assemblies which properties fit the needs to encode cellular memory. Here, we review some of the principles of phase separation and the function of membrane-less organelles focusing particularly on their roles during stress response and cellular memory.

Whi3 mnemon association with endoplasmic reticulum membranes confines the memory of deceptive courtship to the yeast mother cell Highlights d Whi3 mnemon associates with endoplasmic reticulum membranes d Diffusion barriers restricts Whi3 mnemon inheritance to the mother cell d Whi3 prion-like domain can assemble in self-templating fibrils in vitro d Whi3 can adopt a prion-like behavior in diffusion barrierdefective cells

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13In response to deceptive courtship, budding yeast cells escape pheromone induced cell cycle 14 arrest through coalescence of the G1/S inhibitor Whi3 into a dominant inactive super-15 assembly. Strikingly, Whi3 super-assemblies remain stable over many cell cycles in the 16 mother cells and are not passed on to the daughter cells. Thereby, Whi3 coalescence encodes 17 memory, conferring to it the property of a mnemon (Whi3 mnem ), a protein which conformational 18 change maintain a trait that is permanent in the mother cell but is not inherited by daughter 19 cells. Mnemons share structural features with prions, which are self-templating protein 20 conformations that are inherited by daughter cells. Yet, how the maintenance and asymmetric 21 inheritance of Whi3 mnem are achieved is unknown. Here, we report that Whi3 mnem is closely 22 associated with endoplasmic reticulum (ER) membranes and retained in the mother cell by 23 the presence of lateral membrane diffusion barriers at the bud neck. Strikingly, barrier defects 24 made Whi3 mnem propagate in a mitotically stable manner, like a prion. Alike Whi3 mnem , 25 transformation of Whi3 into a prion required its poly-glutamine prion-like domain. Thus, we 26 propose that Whi3 mnem is in a self-templating state, lending temporal stability to the memory 27 that it encodes, while its anchorage into the compartmentalized membranes of the ER ensures 28 its confinement in the mother cell and prevents its infectious propagation. These results 29 suggest that confined self-templating super-assembly is a powerful mechanism for the long-30 term encoding of information. 31 65 et al., 2001). The function of Whi3 that has been studied the most is the regulation of the G1/S 66 transition of the cell cycle through binding and inhibiting the translation of the mRNA that 67 encodes the G1 cyclin CLN3. This inhibition ensures that entry into S phase is delayed until 68 cells reach a critical size. The prion-like domains of Whi3 are required for Whi3 to adopt a 69 conformation that releases Whi3's inhibition on CLN3 mRNA and allows a long-lasting 70 phenotypic switch. Upon exposure to mating pheromone, haploid yeast cells arrest in the G1 71 phase of the cell cycle and grow towards the source of pheromone. This cytoplasmic projection 72 is termed a shmoo. After prolonged exposure of pheromone without a mating partner in reach, 73 yeast cells become refractory to the pheromone signal and resume their cell cycle (Caudron 74 and Barral, 2013; Moore, 1984). They switch from a shmooing phase to a budding phase. 75Remarkably, once established, this pheromone refractory state is stable, lending memory to 76 the cell that there is no partner available. As a consequence, these cells keep on budding for 77 the remainder of their life span even in the presence of mating pheromone. Strikingly, daughter 78 cells do not inherit this adaptation and restore their ability to shmoo in response to pheromone 79 upon separation from their mother cell (Caudron and Barral, 2013). Whi3's prion-like domains 80...

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