title: Mevalonate Pathway Regulates Cell Size Homeostasis and Proteostasis through Autophagy.
abstract: 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.
authors.affiliation: Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee, DD1 5EH Dundee, Scotland, UK. Electronic address: t.miettinen@dundee.ac.uk.
authors.forename: Teemu P
authors.initials: TP
authors.lastname: Miettinen
authors.affiliation: Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee, DD1 5EH Dundee, Scotland, UK. Electronic address: m.bjorklund@dundee.ac.uk.
authors.forename: Mikael
authors.initials: M
authors.lastname: Björklund
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D019169:Jurkat Cells; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008798:Mevalonic Acid / Q000378:metabolism / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D054876:Prenylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008798:Mevalonic Acid; D034741:RNA, Small Interfering; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins