HMG-CoA reductase promotes protein prenylation and therefore is indispensible for T-cell survival.
Sonja M LacherJulia BruttgerBettina KaltJean BertheletKrishnaraj RajalingamSimone WörtgeEsther Von StebutPublished in: Cell death & disease (2017)
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.
Keyphrases
- regulatory t cells
- cell death
- cardiovascular disease
- binding protein
- protein protein
- low density lipoprotein
- drug induced
- cell cycle arrest
- anti inflammatory
- poor prognosis
- early onset
- amino acid
- induced apoptosis
- dendritic cells
- cell therapy
- oxidative stress
- single cell
- small molecule
- cell proliferation
- peripheral blood
- fatty acid
- mesenchymal stem cells
- bone marrow
- celiac disease