Discovery of Novel Splice Variants and Regulatory Mechanisms for Microsomal Triglyceride Transfer Protein in Human Tissues.
Discovery of Novel Splice Variants and Regulatory Mechanisms for Microsomal Triglyceride Transfer Protein in Human Tissues.
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人体组织中微粒体甘油三酯转移蛋白的新型剪接变体和调节机制的发现。
DOI：
10.1038/srep27308
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发表时间：
2016
影响因子：
4.6
通讯作者：
Swift,LarryL
中科院分区：
文献类型：
--
作者：
Suzuki,Takashi;Swift,LarryL
微粒体甘油三酯转移蛋白（MTP）是一种独特的脂质转移蛋白，对肝脏和肠道组装富含甘油三酯的脂蛋白至关重要。先前在小鼠中的研究鉴定了具有替代第一外显子的MTP剪接变体。人类MTP的剪接变体尚未报道。使用PCR方法，我们已经在人体组织中鉴定了两种剪接变体，我们将其命名为MTP-B和MTP-C。MTP-B具有独特的第一外显子（Ex 1B），位于典型MTP（MTP-A）第一外显子（Ex 1A）上游10.5 kb处; MTP-C包含MTP-A和MTP-B的第一外显子。MTP-B在许多组织中发现，而MTP-C在脑和睾丸中突出。MTP-B不编码蛋白质; MTP-C编码与MTP-A相同的蛋白质，尽管MTP-C的翻译被其5′-UTR内的调控元件强烈抑制。使用荧光素酶测定，我们证明了外显子1B上游的启动子区是相当足够的驱动MTP的表达。我们的结论是，选择性剪接通过引入不同的启动子区域和独特的5′-UTR（包含改变翻译效率的元件），使细胞能够优化MTP活性，从而在调节细胞MTP水平方面发挥关键作用。
Microsomal triglyceride transfer protein (MTP) is a unique lipid transfer protein essential for the assembly of triglyceride-rich lipoproteins by the liver and intestine. Previous studies in mice identified a splice variant of MTP with an alternate first exon. Splice variants of human MTP have not been reported. Using PCR approaches we have identified two splice variants in human tissues, which we have named MTP-B and MTP-C. MTP-B has a unique first exon (Ex1B) located 10.5 kb upstream of the first exon (Ex1A) for canonical MTP (MTP-A); MTP-C contains both first exons for MTP-A and MTP-B. MTP-B was found in a number of tissues, whereas MTP-C was prominent in brain and testis. MTP-B does not encode a protein; MTP-C encodes the same protein encoded by MTP-A, although MTP-C translation is strongly inhibited by regulatory elements within its 5′-UTR. Using luciferase assays, we demonstrate that the promoter region upstream of exon 1B is quite adequate to drive expression of MTP. We conclude that alternate splicing plays a key role in regulating cellular MTP levels by introducing distinct promoter regions and unique 5′-UTRs, which contain elements that alter translation efficiency, enabling the cell to optimize MTP activity.