Stimulation of PrPC retrograde transport toward the endoplasmic reticulum increases accumulation of PrPSc in prion-infected cells
Stimulation of PrPC retrograde transport toward the endoplasmic reticulum increases accumulation of PrPSc in prion-infected cells
复制标题
DOI：
10.1074/jbc.m205110200
复制
发表时间：
2002-10-11
影响因子：
4.8
通讯作者：
Lehmann, S
中科院分区：
文献类型：
--
作者：
Béranger, F;Mangé, A;Lehmann, S
朊病毒病是一种致命的传染性神经退行性疾病，其特征是异常折叠的同种型的积累。细胞朊病毒蛋白（PrPC）的蛋白质，表示为PrPSc。为了确定参与PrPSc形成的细胞内细胞器，我们研究了Ras相关的GTP结合蛋白Rab 4和Rab 6a在朊病毒蛋白的细胞内运输和PrPSc的产生中的作用。当显性负性Rab 4突变体或组成型活性GTP结合Rab 6a蛋白在朊病毒感染的神经母细胞瘤N2 a细胞中过表达时，PrPSc形成显著增加。通过免疫荧光和细胞分级分离研究，我们已经表明，Rab 6a-GTP的表达使PrP在细胞内隔室中离域，导致内质网中的积累。这些结果表明，朊病毒蛋白可以进行逆行运输向内质网，这间室可能发挥重要作用PrPSc转换。
Prion diseases are fatal and transmissible neurodegenerative disorders characterized by the accumulation of an abnormally folded isoform. of the cellular prion protein (PrPC) denoted PrPSc. To identify intracellular organelles involved in PrPSc formation, we studied the role of the Ras-related GTP-binding proteins Rab4 and Rab6a in intracellular trafficking of the prion protein and production of PrPSc. When a dominant-negative Rab4 mutant or a constitutively active GTP-bound Rab6a protein was overexpressed in prion-infected neuroblastoma N2a cells, there was a marked increase of PrPSc formation. By immunofluoreseence and cell fractionation studies, we have shown that expression of Rab6a-GTP delocalizes PrP within intracellular compartments, leading to an accumulation in the endoplasmic reticulum. These results suggest that prion protein can be subjected to retrograde transport toward the endoplasmic reticulum and that this compartment may play a significant role in PrPSc conversion.