Abstract
How cells coordinate growth and division is key for size homeostasis. Phosphorylation by G1-CDK of Whi5/Rb inhibitors of SBF/E2F transcription factors triggers irreversible S-phase entry in yeast and metazoans, but why this occurs at a given cell size is not fully understood. We show that the yeast Rim15-Igo1,2 pathway, orthologous to Gwl-Arpp19/ENSA, is up-regulated in early G1 and helps promoting START by preventing PP2ACdc55 to dephosphorylate Whi5. RIM15 overexpression lowers cell size while IGO1,2 deletion delays START in cells with low CDK activity. Deletion of WHI5, CDC55 and ectopic CLN2 expression suppress the START delay of igo1,2∆ cells. Rim15 activity increases after cells switch from fermentation to respiration, where Igo1,2 contribute to chromosome maintenance. Interestingly Cln3-Cdk1 also inhibits Rim15 activity, which enables homeostatic control of Whi5 phosphorylation and cell cycle entry. We propose that Rim15/Gwl regulation of PP2A plays a hitherto unappreciated role in cell size homeostasis during metabolic rewiring of the cell cycle.
Highlights
The size and shape of cells are main determinants of their function
In S. cerevisiae, a large body of evidence indicates that the earliest G1 cyclin, Cln3, fulfills the criteria required for a size sensor: it has a short half life and its abundance scales with protein synthesis rates; increased Cln3 dosage makes cells smaller, and low Cln3 makes cells larger
Since major cell cycle transitions are often controlled by multisite phosphorylation of key substrates (Holt et al, 2009; Nash et al, 2001), we reasoned that the Rim15/Gwl phosphatase-regulating pathway might come into play only when CDK activity decreases below a threshold where unrestrained phosphatase activity would prevent CDKs to fully phosphorylate these key substrates
Summary
The size and shape of cells are main determinants of their function. Despite large differences in cell sizes within and between species, cells of a given cell type usually adopt a homogenous size suited to their nutritional environment, a property called cell size homeostasis. Even after stress-induced cell size variations, cells return to their original size within a few cell divisions (Fantes, 1977) Such size correction mechanisms imply that cells have means to sense their size and to change their division rate (Ginzberg et al, 2015; Jorgensen and Tyers, 2004). Budding yeast and mammalian cells coordinate cell growth and cell division mostly in G1 at a point called ‘START’ or ‘Restriction point’, respectively, after which they become committed to undergo cell division (Johnston et al, 1977; Killander and Zetterberg, 1965). Several models have been proposed to explain how Cln could trigger START at a specific cell size: (i) rise in nuclear Cln (Jorgensen et al, 2007), (ii) Cln sequestration in the endoplasmic reticulum (Verges et al, 2007; Yahya et al, 2014), (iii) titration of Cln against fixed number of SBF sites (Wang et al, 2009) or (iv)
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