HMG-CoA reductase promotes protein prenylation and therefore is indispensible for T-cell survival
HMG-CoA reductase promotes protein prenylation and therefore is indispensible for T-cell survival
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DOI：
10.1038/cddis.2017.221
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发表时间：
2017-05-01
影响因子：
9
通讯作者：
Waisman, Ari
中科院分区：
文献类型：
--
作者：
Lacher, Sonja M.;Bruttger, Julia;Waisman, Ari
他汀类药物是一个成熟的药物家族，通过竞争性抑制酶3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）降低胆固醇水平。此外，他汀类药物对T细胞的多效性抗炎作用使其成为T细胞驱动的自身免疫性疾病的治疗药物。由于他汀类药物不专门靶向HMGCR，因此可能对不同的细胞类型有不同的影响，我们产生了一种新的小鼠品系，允许组织特异性缺失HMGCR。T细胞中HMGCR表达的缺失导致其数量严重减少，剩余的细胞显示活化表型，特别是调节性T细胞（T-CTL）的比例增加。然而，特异性地在T细胞中缺失HMGCR导致严重的自身免疫，这表明该酶对于T细胞的维持也是必需的。我们能够通过添加HMGCR的直接代谢产物，即甲羟戊酸或下游代谢产物香叶基香叶基焦磷酸（其对蛋白质异戊二烯化至关重要）来防止HMGCR缺陷淋巴细胞的死亡。然而，添加胆固醇，这是甲羟戊酸途径的最终产物，并没有抑制细胞死亡，表明蛋白质异戊二烯化，而不是胆固醇生物合成途径是T细胞生存不可或缺的。
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 (T-regs) in particular. However, deletion of HMGCR specifically in T-regs resulted in severe autoimmunity, suggesting that this enzyme is also essential for the maintenance of T-regs. 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.