Association of calnexin with mutant peripheral myelin protein-22 ex vivo:: A basis for "gain-of-function" ER diseases
Association of calnexin with mutant peripheral myelin protein-22 ex vivo:: A basis for "gain-of-function" ER diseases
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DOI：
10.1073/pnas.152621799
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发表时间：
2002-07-23
影响因子：
11.1
通讯作者：
Snipes, GJ
中科院分区：
文献类型：
--
作者：
Dickson, KM;Bergeron, JJM;Snipes, GJ
雪旺细胞来源的外周髓磷脂蛋白 22 (PMP-22) 当突变或过度表达时会导致遗传性神经病，并具有先前无法解释的“功能获得”内质网 (ER) 保留表型。在野生型坐骨神经中，PMP-22 以特定的、短暂的（t(1/2) 大约 11 分钟）和寡糖加工依赖性方式与凝集素伴侣钙连接蛋白 (CNX) 结合，但不与钙网蛋白或 BiP 结合。在 Trembler-J (Tr-J) 坐骨神经中，发现突变型 PMP-22 与 CNX 的长时间关联（t(1/2) > 60 分钟）。在过表达 PMP-22(Tr-J) 的 293A 细胞中，CNX 和 PMP-22 共定位于在电子显微镜水平上鉴定为髓磷脂样图形的大型细胞内结构中，其中 CNX 定位于依赖于 PMP-22 糖基化的结构中。类似的细胞内髓磷脂样图形也存在于纯合 Trembler-J 小鼠的坐骨神经雪旺细胞中，没有检测到应激反应途径的激活，如从 BiP 和 CHOP 表达推断的那样。 CNX 在细胞内髓磷脂样结构中的隔离可能与常染色体显性夏科-玛丽-图思相关神经病有关。
Schwann cell-derived peripheral myelin protein-22 (PMP-22) when mutated or overexpressed causes heritable neuropathies with a previously unexplained "gain-of-function" endoplasmic reticulum (ER) retention phenotype. In wild-type sciatic nerves, PMP-22 associates in a specific, transient (t(1/2) approximate to 11 min), and oligosaccharide processing-dependent manner with the lectin chaperone calnexin (CNX), but not calreticulin nor BiP. In Trembler-J (Tr-J) sciatic nerves, prolonged association of mutant PMP-22 with CNX is found (t(1/2) > 60 min). In 293A cells overexpressing PMP-22(Tr-J), CNX and PMP-22 colocalize in large intracellular structures identified at the electron microscopy level as myelin-like figures with CNX localization in the structures dependent on PMP-22 glucosylation. Similar intracellular myelin-like figures were also present in Schwann cells of sciatic nerves from homozygous Trembler-J mice with no detectable activation of the stress response pathway as deduced from BiP and CHOP expression. Sequestration of CNX in intracellular myelin-like figures may be relevant to the autosomal dominant Charcot-Marie-Tooth-related neuropathies.