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

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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Crossref · 10.1096/fj.04-2702fje

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  • Statins inhibit synthesis of important isoprenoids such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are lipid attachments for the γ subunit of heterotrimeric G-proteins, Ras, and Ras-like proteins.

    “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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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
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
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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