Isoprenoid alcohols restore protein isoprenylation in a time‐dependent manner independent of protein synthesis

Ownby, Susan E.; Hohl, Raymond J.

doi:10.1007/s11745-003-1123-8

Cited by 15 publications

(10 citation statements)

References 34 publications

(49 reference statements)

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“…Therefore, we treated HeLa cells with compactin to block prenylation of Rabs [13] and then incubated cells with geranylgeraniol (GGOH) for different time periods. GGOH was shown to convert to GGPP in the cells [14,15] leading to a subsequent rescue of the prenylation block in the absence of de novo phosphoisoprenoid synthesis and subsequently restores prenylation of Rabs (Figure 5B and Supporting Results S1). Assuming the existence of a Rab prenylation hierarchy, one would expect Rab proteins with higher affinity for REPs to be prenylated faster than the lower affinity Rabs.…”

Section: Resultsmentioning

confidence: 99%

Rab GTPase Prenylation Hierarchy and Its Potential Role in Choroideremia Disease

et al. 2013

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Protein prenylation is a widespread post-translational modification in eukaryotes that plays a crucial role in membrane targeting and signal transduction. RabGTPases is the largest group of post-translationally C-terminally geranylgeranylated. All Rabs are processed by Rab geranylgeranyl-transferase and Rab escort protein (REP). Human genetic defects resulting in the loss one of two REP isoforms REP-1, lead to underprenylation of RabGTPases that manifests in retinal degradation and blindness known as choroideremia. In this study we used a combination of microinjections and chemo-enzymatic tagging to establish whether Rab GTPases are prenylated and delivered to their target cellular membranes with the same rate. We demonstrate that although all tested Rab GTPases display the same rate of membrane delivery, the extent of Rab prenylation in 5 hour time window vary by more than an order of magnitude. We found that Rab27a, Rab27b, Rab38 and Rab42 display the slowest prenylation in vivo and in the cell. Our work points to possible contribution of Rab38 to the emergence of choroideremia in addition to Rab27a and Rab27b.

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Section: Resultsmentioning

confidence: 99%

Rab GTPase Prenylation Hierarchy and Its Potential Role in Choroideremia Disease

et al. 2013

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“…Furthermore, statins reduce the up-regulation of GM1 during T cell activation and prevent the association of Lck and LAT with MR in stimulated T cells. Earlier reports suggested several molecular mechanisms such as an inhibition of HMG CoA reductase (29), prenylation (30), coactivation by integrins like LFA-1 (23), Ag presentation (9), and modulation of lipid microdomains (20,21). The variety of mechanisms might also depend on the used statin concentration.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin Inhibits T Cell Activation through 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase without Decreasing Cholesterol Synthesis

Blank

Schiller

Krienke

et al. 2007

The Journal of Immunology

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The localization of the TCR and other signaling molecules in membrane rafts (MR) is essential for the activation of T lymphocytes. MR are stabilized by sphingolipids and cholesterol. Activation of T lymphocytes leads to the confluence of small MR and the formation of an immunological synapse that is essential for sustained activation and proliferation. In this study, we investigated the effect of statins on MR and T cell activation in superantigen-stimulated human PBMC. Atorvastatin significantly inhibited cellular activation and proliferation. The binding of cholera toxin B subunit to isolated MR and to whole cells was inhibited by low doses of statins. Statins reduce the association of critical signaling proteins such as Lck and linker of activation in T cells with MR in stimulated T cells. The expression of activation markers CD69 and CD25 was inhibited. Several statin-mediated mechanisms, such as a lower stimulation with MHC-II, an inhibition of costimulation by direct binding of statins to LFA-1, a reduced secretion of cytokines, or a depletion of cellular cholesterol pools, were excluded. Inhibition of protein prenylation had a similar effect on T cell proliferation, suggesting that a reduced protein prenylation might contribute to the statin-mediated inhibition of T cell activation. Statins induce both lower levels of low-density lipoprotein cholesterol and inhibition of T cell activation, which might contribute to an inhibition of atherosclerosis.

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“…Farnesol (FOH) and geranylgeraniol (GGOH) are produced by dephosphorylation of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, respectively, although they are in turn phosphorylated to their pyrophosphates [3-5]. The two isoprenoids are increasingly known to display multiple functions.…”

Section: Introductionmentioning

confidence: 99%

Roles of rat and human aldo–keto reductases in metabolism of farnesol and geranylgeraniol

Endo

Matsunaga

Ohta

et al. 2011

Chemico-Biological Interactions

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Farnesol (FOH) and geranylgeraniol (GGOH) with multiple biological actions are produced from the mevalonate pathway, and catabolized into farnesoic acid and geranylgeranoic acid, respectively, via the aldehyde intermediates (farnesal and geranylgeranial). We investigated the intracellular distribution, sequences and properties of the oxidoreductases responsible for the metabolic steps in rat tissues. The oxidation of FOH and GGOH into their aldehyde intermediates were mainly mediated by alcohol dehydrogenases 1 (in the liver and colon) and 7 (in the stomach and lung), and the subsequent step into the carboxylic acids was catalyzed by a microsomal aldehyde dehydrogenase. In addition, high reductase activity catalyzing the aldehyde intermediates into FOH (or GGOH) was detected in the cytosols of the extra-hepatic tissues, where the major reductase was identified as aldo-keto reductase (AKR) 1C15. Human reductases with similar specificity were identified as AKR1B10 and AKR1C3, which most efficiently reduced farnesal and geranylgeranial among seven enzymes in the AKR1A-1C subfamilies. The overall metabolism from FOH to farnesoic acid in cultured cells was significantly decreased by overexpression of AKR1C15, and increased by addition of AKR1C3 inhibitors, tolfenamic acid and R-flurbiprofen. Thus, AKRs (1C15 in rats, and 1B10 and 1C3 in humans) may play an important role in controlling the bioavailability of FOH and GGOH.

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Isoprenoid alcohols restore protein isoprenylation in a time‐dependent manner independent of protein synthesis

Cited by 15 publications

References 34 publications

Rab GTPase Prenylation Hierarchy and Its Potential Role in Choroideremia Disease

Rab GTPase Prenylation Hierarchy and Its Potential Role in Choroideremia Disease

Atorvastatin Inhibits T Cell Activation through 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase without Decreasing Cholesterol Synthesis

Roles of rat and human aldo–keto reductases in metabolism of farnesol and geranylgeraniol

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