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

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.

The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway

“…It seems likely that inhibition of protein prenylation should impact many cellular processes and organelles besides the mitochondria. Indeed, statins strongly induce the UPR er in C. elegans, suggesting not only that the endoplasmic reticulum is impacted by inhibition of the mevalonate pathway, but also that the cell is able to activate an appropriate stress response (9). The mitochondrial stress caused by statins is therefore unusual in that it does not result in the activation of UPR mt even though it is evidently the required protective response.…”

“…Plates with different concentrations of fluvastatin (brand Lescol; Novartis) were made as described in a previous study (9). Briefly, 40 mg of fluvastatin was dissolved in water (2.31 mL) and spun at 5,000 × g to separate insoluble components.…”

“…1A) (6)(7)(8)(9). In C. elegans, statins cause decreased protein prenylation, induction of the endoplasmic reticulum unfolded protein response (UPR er ), growth arrest, and lethality; these are all on-target effects of statins because they can be abrogated by the inclusion of mevalonate in the culture medium (9).…”

“…1A) (6)(7)(8)(9). In C. elegans, statins cause decreased protein prenylation, induction of the endoplasmic reticulum unfolded protein response (UPR er ), growth arrest, and lethality; these are all on-target effects of statins because they can be abrogated by the inclusion of mevalonate in the culture medium (9). To identify cellular processes that can compensate for a reduced output from the mevalonate pathway, we isolated C. elegans mutants that are resistant to statins and found that these are all gain-of-function (gof) mutations in the protein ATFS-1, the key regulator of the mitochondrial unfolded protein response (UPR mt ) (10)(11)(12)(13).…”

Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy-based unconventional secretory pathway in Alzheimer disease

“…Although it is indirect evidence, previous studies have shown that statin treatment increases IDE secretion, and inhibits protein prenylation. 35,41 Whether IDE secretion by statin treatment occurs through same pathway as Ab treatment should be investigated. Further, how IDE inside the lysosome is transported to the extracellular medium needs to be determined.…”