CPEB2-dependent translation of long 3′-UTR Ucp1 mRNA promotes thermogenesis in brown adipose tissue
CPEB2-dependent translation of long 3′-UTR Ucp1 mRNA promotes thermogenesis in brown adipose tissue
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DOI：
10.15252/embj.201899071
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发表时间：
2018-10-15
期刊：
影响因子：
11.4
通讯作者：
Huang, Yi-Shuian
中科院分区：
文献类型：
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作者：
Chen, Hui-Feng;Hsu, Chen-Ming;Huang, Yi-Shuian
线粒体质子转运体解偶联蛋白1(UCP1)在棕色脂肪组织(BAT)中的表达是哺乳动物产热所必需的。虽然人类UCP1 mRNA只以长形式存在，但交替的聚腺苷酸化作用在小鼠身上产生了两种不同的异构体，10%的UCP1 mRNA存在于长形式(Ucp1L)中，而类似于90%的UCP1 mRNA存在于短形式(Ucp1S)中。我们建立了一个只表达Ucp1S的小鼠模型，发现由于UCP1蛋白水平下降60%，它显示出产热功能受损，这表明Ucp1L的翻译效率高于Ucp1S。此外，我们还发现，β3肾上腺素能受体信号通路促进了小鼠Ucp1L和人Ucp1的翻译，这种作用依赖于胞浆多聚腺苷酸化元件结合蛋白2(CPEB2)。CPEB2基因敲除小鼠表现出UCP1水平降低和蝙蝠产热能力受损，这可以通过异位表达CPEB2来挽救。因此，CPEB2激活的Long 3‘-UTRUcp1mRNA翻译在人类产生UCP1用于产热方面可能是保守的和重要的。
Expression of mitochondrial proton transporter uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is essential for mammalian thermogenesis. While human UCP1 mRNA exists in a long form only, alternative polyadenylation creates two different isoforms in mice with 10% of UCP1 mRNA found in the long form (Ucp1L) and similar to 90% in the short form (Ucp1S). We generated a mouse model expressing only Ucp1S and found that it showed impaired thermogenesis due to a 60% drop in UCP1 protein levels, suggesting that Ucp1L is more efficiently translated than Ucp1S. In addition, we found that beta 3 adrenergic receptor signaling promoted the translation of mouse Ucp1L and human Ucp1 in a manner dependent on cytoplasmic polyadenylation element binding protein 2 (CPEB2). CPEB2-knockout mice showed reduced UCP1 levels and impaired thermogenesis in BAT, which was rescued by ectopic expression of CPEB2. Hence, long 3 '-UTR Ucp1 mRNA translation activated by CPEB2 is likely conserved and important in humans to produce UCP1 for thermogenesis.