LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of β-Glucocerebrosidase
LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of β-Glucocerebrosidase
复制标题
DOI：
10.1016/j.cell.2007.10.018
复制
发表时间：
2007-11-16
期刊：
影响因子：
64.5
通讯作者：
Saftig, Paul
中科院分区：
文献类型：
--
作者：
Reczek, David;Schwake, Michael;Saftig, Paul
-葡萄糖脑苷酶，戈谢病中有缺陷的酶，是独立于甘露糖-6-磷酸受体的溶酶体。亲和层析实验表明，溶酶体整体膜蛋白LIMP-2是β -葡萄糖脑苷酶的特异性结合伙伴。这种相互作用涉及管腔域内的线圈-线圈域。在limp -2缺陷小鼠组织中，β -葡萄糖脑苷酶活性和蛋白水平严重降低。从这些小鼠分离的成纤维细胞和巨噬细胞分析表明，大部分β -葡萄糖脑苷酶被分泌。体内β -葡萄糖脑苷酶的错误分类也很明显，因为与野生型相比，limp -2缺陷小鼠血清中的蛋白质和活性水平显着更高。在缺乏LIMP-2的成纤维细胞中重建LIMP-2导致β -葡萄糖脑苷酶水平和分布的恢复。LIMP-2的表达也导致β -葡萄糖脑苷酶内质网保留突变体的溶酶体转运。这些数据支持了LIMP-2作为β -葡萄糖脑苷酶的甘露糖-6-磷酸非依赖性转运受体的作用。
beta-glucocerebrosidase, the enzyme defective in Gaucher disease, is targeted to the lysosome independently of the mannose-6-phosphate receptor. Affinity-chromatography experiments revealed that the lysosomal integral membrane protein LIMP-2 is a specific binding partner of beta-glucocerebrosidase. This interaction involves a coiled-coil domain within the lumenal domain. beta-glucocerebrosidase activity and protein levels were severely decreased in LIMP-2-deficient mouse tissues. Analysis of fibroblasts and macrophages isolated from these mice indicated that the majority of beta-glucocerebrosidase was secreted. Missorting of beta-glucocerebrosidase was also evident in vivo, as protein and activity levels were significantly higher in sera from LIMP-2-deficient mice compared to wild-type. Reconstitution of LIMP-2 in LIMP-2-deficient fibroblasts led to a rescue of beta-glucocerebrosidase levels and distribution. LIMP-2 expression also led to lysosomal transport of a beta-glucocerebrosidase endoplasmic reticulum retention mutant. These data support a role for LIMP-2 as the mannose-6-phosphate-independent trafficking receptor for beta-glucocerebrosidase.