Cited by 154Protein Kinase Regulation and GTPase SignalingCancer, Lipids, and MetabolismSphingolipid Metabolism and Signaling

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Simvastatin inhibits T‐cell activation by selectively impairing the function of Ras superfamily GTPases

Ghittoni, Raffaella, Patrussi, Laura, Pirozzi, Katja, Pellegrini, Michela, Lazzerini, Pietro E., Capecchi, P. Leopoldo, Pasini, Franco Laghi, Baldari, Cosima T.·2005·The FASEB Journal

DOI 10.1096/fj.04-2702fje

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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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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)
ORCID: Patrussi, Laura
Lazzerini, Pietro E.
Capecchi, P. Leopoldo
Pasini, Franco Laghi
Baldari, Cosima T.
Venue: The FASEB Journal
Publisher: Wiley
Published: 2005-01-27
Volume: 19
Issue: 6
Pages: 1-24
ISSN: 0892-6638 (ISSN-L)
1530-6860
DOI: 10.1096/fj.04-2702fje
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: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
doi.wiley.com/10.1002/tdm_license_1.1 (tdm)
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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Simvastatin inhibits T‐cell activation by selectively impairing the function of Ras superfamily GTPases

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