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Mevalonate Pathway Regulates Cell Size Homeostasis and Proteostasis through Autophagy

Teemu P Miettinen1, Mikael Björklund1

  • 1Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee, DD1 5EH Dundee, Scotland, UK.

Cell Reports
|December 22, 2015
PubMed

Insights

Statins, used to inhibit the mevalonate pathway, decrease cell proliferation and increase cell size and protein density. This occurs via geranylgeranylation of RAB11, regulating autophagy and cell size homeostasis.

Area of Science:

  • Cell Biology
  • Metabolic Pathways
  • Drug Discovery

Background:

  • Cell size homeostasis relies on balancing cell growth and proliferation.
  • The role of metabolic pathways in maintaining this balance is not well understood.

Purpose of the Study:

  • To investigate the effects of clinically used drugs on cell size.
  • To identify metabolic regulators of cell size and proteostasis.

Main Methods:

  • Screening a library of clinical drug molecules for their impact on cell size.
  • Utilizing various cell types, including primary human cells.
  • Investigating the role of geranylgeranylation and the small GTPase RAB11.

Main Results:

  • Statins, inhibitors of the mevalonate pathway, were found to reduce cell proliferation.
  • Statins increased cell size and cellular protein density across multiple cell types.
  • Mevalonate pathway's influence on cell size and protein density is mediated by RAB11 geranylgeranylation, impacting autophagic flux.

Conclusions:

  • The mevalonate pathway is identified as a key metabolic regulator of autophagy.
  • Inhibition of an anabolic pathway paradoxically leads to increased cell size and protein density, highlighting complex regulation of proteostasis.

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