Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex
Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex
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DOI：
10.1038/ng1153
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发表时间：
2003-06-01
期刊：
影响因子：
30.8
通讯作者：
Ginsburg, D
中科院分区：
文献类型：
--
作者：
Zhang, B;Cunningham, MA;Ginsburg, D
LMAN1（也称为ERGIC - 53）突变导致因子V和因子VIII联合缺乏症（F5F8D），这是一种常染色体隐性出血性疾病，其特征是两种凝血蛋白协同减少（1）。LMAN1是一种定位于内质网 - 高尔基体中间腔室（ERGIC；参考文献2，3）的甘露糖结合1型跨膜蛋白，这表明F5F8D可能是由于因子V和因子VIII分泌缺陷所致（参考文献4）。注定要分泌的正确折叠的蛋白质在内质网中被包装到COPII包被的囊泡中（5），这些囊泡随后融合形成ERGIC。某些丰富蛋白质的分泌表明存在一种不需要输出信号的默认途径（批量流动；参考文献6，7）。另一种机制涉及在特定货物受体的帮助下对分泌蛋白进行选择性包装（8 - 13）。后一种模型与LMAN1突变导致因子V和因子VIII输出的选择性阻断是一致的。但是，大约30%的F5F8D患者LMAN1水平正常，这表明另一个基因的突变也可能与F5F8D有关（14，15）。在此我们表明，MCFD2的失活突变导致F5F8D，其表型与LMAN1突变所导致的表型无法区分。MCFD2通过与LMAN1直接的、钙依赖的相互作用而定位于ERGIC。这些发现表明，MCFD2 - LMAN1复合物形成了一种特定的货物受体，用于某些选定蛋白质从内质网到高尔基体的运输。
Mutations in LMAN1 (also called ERGIC-53) result in combined deficiency of factor V and factor VIII ( F5F8D), an autosomal recessive bleeding disorder characterized by coordinate reduction of both clotting proteins(1). LMAN1 is a mannose-binding type 1 transmembrane protein localized to the endoplasmic reticulum Golgi intermediate compartment (ERGIC; refs. 2,3), suggesting that F5F8D could result from a defect in secretion of factor V and factor VIII (ref. 4). Correctly folded proteins destined for secretion are packaged in the ER into COPII-coated vesicles(5), which subsequently fuse to form the ERGIC. Secretion of certain abundant proteins suggests a default pathway requiring no export signals (bulk flow; refs. 6,7). An alternative mechanism involves selective packaging of secreted proteins with the help of specific cargo receptors(8-13). The latter model would be consistent with mutations in LMAN1 causing a selective block to export of factor V and factor VIII. But similar to30% of individuals with F5F8D have normal levels of LMAN1, suggesting that mutations in another gene may also be associated with F5F8D(14,15). Here we show that inactivating mutations in MCFD2 cause F5F8D with a phenotype indistinguishable from that caused by mutations in LMAN1. MCFD2 is localized to the ERGIC through a direct, calcium-dependent interaction with LMAN1. These findings suggest that the MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins.