Abstract
Statins are a well-established family of drugs that lower cholesterol levels via the competitive inhibition of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). In addition, the pleiotropic anti-inflammatory effects of statins on T cells make them attractive as therapeutic drugs in T-cell-driven autoimmune disorders. Since statins do not exclusively target HMGCR and thus might have varying effects on different cell types, we generated a new mouse strain allowing for the tissue-specific deletion of HMGCR. Deletion of HMGCR expression in T cells led to a severe decrease in their numbers with the remaining cells displaying an activated phenotype, with an increased proportion of regulatory T cells (Tregs) in particular. However, deletion of HMGCR specifically in Tregs resulted in severe autoimmunity, suggesting that this enzyme is also essential for the maintenance of Tregs. We were able to prevent the death of HMGCR-deficient lymphocytes by the addition of either the direct metabolite of HMGCR, namely mevalonate, or the downstream metabolite geranylgeranyl pyrophosphate, which is essential for protein prenylation. However, the addition of cholesterol, which is the final product of the mevalonate pathway, did not inhibit cell death, indicating that protein prenylation rather than the cholesterol biosynthesis pathway is indispensible for T-cell survival.
Highlights
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) is an endoplasmatic reticulum residing enzyme, which catalyzes the rate-limiting step of cholesterol biosynthesis within the mevalonate pathway.[1]
The gene Hmgcr is located on chromosome 13 in mice and consists of 20 exons, which can be expressed as 11 different splice variants, 7 of which are protein coding
Using a novel mouse strain that allows us to conditionally delete HMGCR, we found that HMGCR is critically important for the survival of T cells
Summary
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) is an endoplasmatic reticulum residing enzyme, which catalyzes the rate-limiting step of cholesterol biosynthesis within the mevalonate pathway.[1]. It became evident that statins have pleiotropic immunological effects[4,5,6] and can even prevent tumor development.[7,8] When used to treat mice in a model of multiple sclerosis, statins were shown to ameliorate the disease.[6] Disease reduction was attributed to reduced proliferation of the self-reactive T cells and a shift from proinflammatory interferon-γ (IFNγ) producing TH1 cells to antiinflammatory IL-4 producing TH2 cells and a subsequent decrease in inflammation of the central nervous system These effects of statin treatment are most likely not mediated by decreased cholesterol levels, but rather could be due to decreased protein prenylation, another HMGCR-. Some important prenylated proteins include members of the Ras superfamily of small GTPases, such as Ras and Rho, involved in proliferation and differentiation processes of cells.[2] To better understand the role of statins in autoimmunity and elucidate their effects on HMGCR and other putative targets, we generated a new mouse strain that enables tissue-specific deletion of HMGCR via Cre/loxP system. Our data demonstrate that HMGCR is indispensible for the survival of T cells via the protein prenylation pathway
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