Reduced cholesterol and triglycerides in mice with a mutation in Mia2, a liver protein that localizes to ER exit sites
Reduced cholesterol and triglycerides in mice with a mutation in Mia2, a liver protein that localizes to ER exit sites
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DOI：
10.1194/jlr.m017277
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发表时间：
2011-10-01
影响因子：
6.5
通讯作者：
Gekakis, Nicholas
中科院分区：
文献类型：
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作者：
Pitman, Jeffrey L.;Bonnet, David J.;Gekakis, Nicholas
通过对小鼠的正向遗传筛选，发现了一种隐性突变（沙发土豆，cpto），它可以显著降低所有脂蛋白类的血浆胆固醇水平。cpto突变改变了Mia 2蛋白的Src同源结构域3（SH 3）结构域中高度保守的残基。全长肝Mia 2在结构和功能上类似于相关的Mia 3蛋白。Mia 2定位于内质网（ER）出口位点，表明在引导蛋白质从ER到高尔基体的作用。与Mia 3蛋白类似，Mia 2的胞质C末端直接与COPII蛋白Sec 23和Sec 24相互作用，而其内腔SH 3结构域可能促进与分泌性货物的相互作用。血浆分级显示Mia 2（cpto/cpto）小鼠具有较低的循环VLDL、LDL、HDL和甘油三酯。因此，Mia 2是一种新型的肝脏ER-高尔基体运输蛋白，可调节胆固醇代谢。皮特曼，J.L.，D.邦纳湖K. Curtiss和N. Gekakis。Mia 2突变小鼠的胆固醇和甘油三酯降低，Mia 2是一种定位于ER出口位点的肝脏蛋白。J. Lipid Res. 2011. 52：1775-1786。
Through forward genetic screening in the mouse, a recessive mutation (couch potato, cpto) has been discovered that dramatically reduces plasma cholesterol levels across all lipoprotein classes. The cpto mutation altered a highly conserved residue in the Src homology domain 3 (SH3) domain of the Mia2 protein. Full-length hepatic Mia2 structurally and functionally resembled the related Mia3 protein. Mia2 localized to endoplasmic reticulum (ER) exit sites, suggesting a role in guiding proteins from the ER to the Golgi. Similarly to the Mia3 protein, Mia2's cytosolic C terminus interacted directly with COPII proteins Sec23 and Sec24, whereas its lumenal SH3 domain may facilitate interactions with secretory cargo. Fractionation of plasma revealed that Mia2(cpto/cpto) mice had lower circulating VLDL, LDL, HDL, and triglycerides. Mia2 is thus a novel, hepatic, ER-to-Golgi trafficking protein that regulates cholesterol metabolism.-Pitman, J. L., D. J. Bonnet, L. K. Curtiss, and N. Gekakis. Reduced cholesterol and triglycerides in mice with a mutation in Mia2, a liver protein that localizes to ER exit sites. J. Lipid Res. 2011. 52: 1775-1786.