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Simvastatin inhibits T‐cell activation by selectively impairing the function of Ras superfamily GTPases
Abstract
Statins are widely used hypocholesterolemic drugs that inhibit 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase, a rate‐limiting enzyme of the mevalonate pathway whose biosynthetic end product is cholesterol. In addition to lowering circulating cholesterol, statins perturb the composition of cell membranes, resulting in disruption of lipid rafts, which function as signaling platforms in immunoreceptor signaling. Furthermore, by inhibiting protein prenylation, a process also dependent on mevalonate, statins block membrane targeting and hence activity of small GTPases, which control multiple pathways triggered by these receptors. T‐cell activation is crucially dependent on Ras, Rho and Rab GTPases. Furthermore TCR signaling is orchestrated at lipid rafts, identifying T‐cells as potential cellular targets of statins. Here we report that simvastatin suppresses T‐cell activation and proliferation as the result of its capacity to inhibit HMG‐CoA reductase. T‐cell treatment with simvastatin does not affect intracellular cholesterol levels or raft integrity nor, accordingly, the initial tyrosine phosphorylation‐dependent cascade. Conversely, inhibition of protein prenylation by simvastatin results in a dramatic impairment in the pathways regulated by small GTPases, including the Ras/MAP kinase pathway, the Rac/stress kinase pathway, and the Rab‐dependent pathway of receptor endocytosis. The results identify Ras superfamily GTPases as strategic molecular targets in T‐cell immunosuppression by statins.
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“Thus, the effects of statins are connected with the inhibition of the synthesis of important isoprenoids, e.g.farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are important lipid attachments for the γ subunit of heterotrimeric G-proteins [12] , guanosine triphosphatebinding protein Ras, and Ras-like proteins (Rho, Rab, Rac, Ral, or Rap) [12][13][14] .”
From Statins as antifungal agents (2011) · cites this paper as [14]
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Metadata
- Authors
- Ghittoni, R., Patrussi, L., Pirozzi, K., Pellegrini, M., Lazzerini, P. E., Capecchi, P. L., Pasini, F. L., & Baldari, C. T.
- Affiliations
- University of Siena (IT)
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2005-01-27
- Volume
- 19
- Issue
- 6
- Pages
- 1-24
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W1993439431
- Cited by
- 154
- References
- 50
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 7 · 2020: 4 · 2019: 5 · 2018: 2 · 2017: 4 · 2016: 3 · 2015: 10 · 2014: 6 · 2013: 8 · 2012: 7
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Use Siena air (University of Siena) (submittedVersion)
- Funders
- Associazione Italiana per la Ricerca sul Cancro
- Fondazione Telethon (E.1161)
- European Commission (QLK2-CT-2002-00620)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- simvastatin, statins, T cell activation, small GTPases, HMG-CoA reductase inhibition, mevalonate pathway, protein prenylation, lipid rafts, T cell receptor signaling, RAS/MAPK pathway, immunosuppression, cholesterol
- MeSH terms
- Endocytosis, Enzyme Inhibitors, Humans, Immunosuppression Therapy, Lymphocyte Activation, Membrane Lipids, Receptors, Antigen, T-Cell, T-Lymphocytes, Signal Transduction, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Jurkat Cells, Simvastatin, Monomeric GTP-Binding Proteins, rab GTP-Binding Proteins, rho GTP-Binding Proteins, Mitogen-Activated Protein Kinases
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