Mevalonate pathway regulates cell size homeostasis and proteostasis through autophagy

Balance between cell growth and proliferation determines cell size homeostasis, but little is known about how metabolic pathways are involved in the maintenance of this balance. Here, we perform a screen with a library of clinically used drug molecules for their effects on cell size. We find that statins, inhibitors of the mevalonate pathway, reduce cell proliferation and increase cell size and cellular protein density in various cell types, including primary human cells. Mevalonate pathway effects on cell size and protein density are mediated through geranylgeranylation of the small GTPase RAB11, which is required for basal autophagic flux. Our results identify the mevalonate pathway as a metabolic regulator of autophagy and expose a paradox in the regulation of cell size and proteostasis, where inhibition of an anabolic pathway can cause an increase in cell size and cellular protein density.