Translational control of human acetyl-CoA carboxylase 1 mRNA is mediated by an internal ribosome entry site in response to ER stress, serum deprivation or hypoxia mimetic CoCl2
Translational control of human acetyl-CoA carboxylase 1 mRNA is mediated by an internal ribosome entry site in response to ER stress, serum deprivation or hypoxia mimetic CoCl2
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DOI：
10.1016/j.bbalip.2018.01.006
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发表时间：
2018-04-01
影响因子：
4.8
通讯作者：
Siculella, Luisa
中科院分区：
文献类型：
--
作者：
Damiano, Fabrizio;Testini, Mariangela;Siculella, Luisa
乙酰辅酶A羧化酶1（acetyl-coA carboxylase 1，ACC 1）是一种催化脂肪酸从头合成的限速酶。越来越多的证据表明，ACC 1易受调节异常的影响，并且在与脂质积累相关的肝脏疾病和几种癌症中过度表达。在本研究中，ACC 1在翻译水平上的调节报告。使用几种实验方法，已经在ACC 1 mRNA的5'非翻译区（5' UTR）中建立了内部核糖体进入位点（IRES）的存在。用插入双顺反子报告载体中的ACC 1 5' UTR进行的转染实验显示，通过帽非依赖性机制，下游顺反子翻译显著增加。内质网（ER）应激条件和相关的未折叠蛋白反应（UPR），由毒胡萝卜素和衣霉素处理触发，导致增加的帽非依赖性翻译的ACC 1 mRNA在HepG 2细胞，尽管在全球蛋白质合成的整体减少。其他应激条件，如血清饥饿和与缺氧模拟剂CoCl 2孵育，在翻译水平上上调HepG 2细胞中ACC 1的表达。总之，这些发现表明，ACC 1 5' UTR中IRES的存在允许ACC 1 mRNA在抑制帽依赖性翻译的条件下翻译。已经讨论了ACC 1的帽非依赖性翻译在几种病理学中的潜在参与，例如肥胖和癌症。
Acetyl-CoA carboxylase 1 (ACC1) is a cytosolic enzyme catalyzing the rate limiting step in de novo fatty acid biosynthesis. There is mounting evidence showing that ACC1 is susceptible to dysregulation and that it is over expressed in liver diseases associated with lipid accumulation and in several cancers. In the present study, ACC1 regulation at the translational level is reported. Using several experimental approaches, the presence of an internal ribosome entry site (IRES) has been established in the 5' untranslated region (5' UTR) of the ACC1 mRNA. Transfection experiments with the ACC1 5' UTR inserted in a dicistronic reporter vector show a remarkable increase in the downstream cistron translation, through a cap-independent mechanism. The endoplasmic reticulum (ER) stress condition and the related unfolded protein response (UPR), triggered by treatment with thapsigargin and tunicamycin, cause an increase of the cap-independent translation of ACC1 mRNA in HepG2 cells, despite the overall reduction in global protein synthesis. Other stress conditions, such as serum starvation and incubation with hypoxia mimetic agent CoCl2, up-regulate ACC1 expression in HepG2 cells at the translational level. Overall, these findings indicate that the presence of an IRES in the ACC1 5' UTR allows ACC1 mRNA translation in conditions that are inhibitory to cap-dependent translation. A potential involvement of the cap-independent translation of ACC1 in several pathologies, such as obesity and cancer, has been discussed.