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Statins inhibit protein lipidation and induce the unfolded protein response in the non-sterol producing nematode Caenorhabditis elegans

Journal article
Authors Catarina Mörck
L. Olsen
C. Kurth
Annelie Persson
N. J. Storm
Emma Svensson
John-Olov Jansson
Marika Hellqvist
Annika Enejder
N. J. Faergeman
Marc Pilon
Published in Proceedings of the National Academy of Sciences
Volume 106
Issue 43
Pages 18285-90
ISSN 0027-8424
Publication year 2009
Published at Department of Cell and Molecular Biology
Institute of Neuroscience and Physiology, Department of Physiology
Pages 18285-90
Language en
Links dx.doi.org/10.1073/pnas.0907117106
Keywords small GTPase; unfolded protein response (UPR); HMG-CoA reductase
Subject categories Cell and molecular biology, Toxicology, Cell Biology, Other pharmacy, Pharmacology and Toxicology

Abstract

Statins are compounds prescribed to lower blood cholesterol in millions of patients worldwide. They act by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway that leads to the synthesis of farnesyl pyrophosphate, a precursor for cholesterol synthesis and the source of lipid moieties for protein prenylation. The nematode Caenorhabditis elegans possesses a mevalonate pathway that lacks the branch leading to cholesterol synthesis, and thus represents an ideal organism to specifically study the noncholesterol roles of the pathway. Inhibiting HMG-CoA reductase in C. elegans using statins or RNAi leads to developmental arrest and loss of membrane association of a GFP-based prenylation reporter. The unfolded protein response (UPR) is also strongly activated, suggesting that impaired prenylation of small GTPases leads to the accumulation of unfolded proteins and ER stress. UPR induction was also observed upon pharmacological inhibition of farnesyl transferases or RNAi inhibition of a specific isoprenoid transferase (M57.2) and found to be dependent on both ire-1 and xbp-1 but not on pek-1 or atf-6, which are all known regulators of the UPR. The lipid stores and fatty acid composition were unaffected in statin-treated worms, even though they showed reduced staining with Nile red. We conclude that inhibitors of HMG-CoA reductase or of farnesyl transferases induce the UPR by inhibiting the prenylation of M57.2 substrates, resulting in developmental arrest in C. elegans. These results provide a mechanism for the pleiotropic effects of statins and suggest that statins could be used clinically where UPR activation may be of therapeutic benefit.

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