Mixed-disulfide folding intermediates between thyroglobulin and endoplasmic reticulum resident oxidoreductases ERp57 and protein disulfide isomerase
Mixed-disulfide folding intermediates between thyroglobulin and endoplasmic reticulum resident oxidoreductases ERp57 and protein disulfide isomerase
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DOI：
10.1128/mcb.25.22.9793-9805.2005
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发表时间：
2005-11-01
影响因子：
5.3
通讯作者：
Arvan, P
中科院分区：
文献类型：
--
作者：
Di Jeso, B;Park, YN;Arvan, P
我们提出了第一个识别的瞬时折叠中间体的内源性甲状腺球蛋白（Tg;甲状腺细胞的大同型二聚体分泌糖蛋白），其中包括混合二硫化物与内源性氧化还原酶服务Tg折叠的需要。二硫键连接的Tg加合物与内质网（ER）氧化还原酶的形成开始于协同作用。ER葡萄糖苷酶活性的抑制阻止了含有ERp 57的Tg加合物亚群的形成，同时导致与蛋白质二硫键异构酶（PDI）的Tg加合物形成增加，加合物分解延迟，Tg单体的氧化折叠受到干扰，Tg二聚化受损，Tg与BiP/GRP 78和GRP 94的结合增加，未折叠蛋白质反应的激活，Tg亚群的ER相关降解增加，部分Tg从ER质量控制中逃逸，游离单体分泌增加，总体Tg分泌减少。这些数据指向与ERp 57氧化还原酶结合的混合二硫化物，钙网蛋白、钙连接蛋白伴侣蛋白充当正常的早期Tg折叠中间体，其可以仅以较低的折叠效率和所得ER应激为代价被PDI加合物“取代”。
We present the first identification of transient folding intermediates of endogenous thyroglobulin (Tg; a large homodimeric secretory glycoprotein of thyrocytes), which include mixed disulfides with endogenous oxidoreductases servicing Tg folding needs. Formation of disulfide-linked Tg adducts with endoplasmic reticulum (ER) oxidoreductases begins cotranslationally. Inhibition of ER glucosidase activity blocked formation of a subgroup of Tg adducts containing ERp57 while causing increased Tg adduct formation with protein disulfide isomerase (PDI), delayed adduct resolution, perturbed oxidative folding of Tg monomers, impaired Tg dimerization, increased Tg association with BiP/GRP78 and GRP94, activation of the unfolded protein response, increased ER-associated degradation of a subpopulation of Tg, partial Tg escape from ER quality control with increased secretion of free monomers, and decreased overall Tg secretion. These data point towards mixed disulfides with the ERp57 oxidoreductase in conjunction with calreticulin, calnexin chaperones acting as normal early Tg folding intermediates that can be "substituted" by PDI adducts only at the expense of lower folding efficiency with resultant ER stress.