Deficiency of the BiP cochaperone ERdj4 causes constitutive endoplasmic reticulum stress and metabolic defects.
Deficiency of the BiP cochaperone ERdj4 causes constitutive endoplasmic reticulum stress and metabolic defects.
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DOI：
10.1091/mbc.e13-06-0319
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发表时间：
2014-02
影响因子：
3.3
通讯作者：
Weaver TE
中科院分区：
文献类型：
--
作者：
Fritz JM;Dong M;Apsley KS;Martin EP;Na CL;Sitaraman S;Weaver TE
Bip辅助伴侣ERdj4通过与ERAD机制结合，从内质网管腔中移除错误折叠的蛋白质。ERdj4的全球缺失导致广泛的结构性内质网应激，小鼠存活率下降和代谢紊乱。这些发现表明ERDj4的伴侣活性对体内内质网的动态平衡很重要。内质网定位的DNAJ4(ERdj4)是一种免疫球蛋白结合蛋白(Bip)辅伴蛋白，也是内质网相关降解(ERAD)途径的组成部分，在内质网应激条件下，它能将未折叠或错误折叠的底物从内质网管腔中移除。为了阐明ERdj4在体内的功能，我们通过基因诱变(GT)破坏了ERdj4基因座，导致ERdj4在捕获等位基因(ERdj4GT/GT)纯合子小鼠中的亚型表达。大约一半的ERdj4GT/GT小鼠在围产期死亡与胎儿生长受限、肝糖原储存减少和低血糖有关。存活的成年小鼠在多种细胞/组织中表现出结构性内质网应激，包括成纤维细胞、肺、肾、唾液腺和胰腺。ERDJ4GT/GT小鼠胰腺β细胞内质网应激升高与β细胞丢失、低胰岛素血症和糖耐量异常有关。总体而言，这些结果表明ERDj4在维持正常胎儿生长和出生后对代谢应激适应的内质网平衡方面发挥着重要作用。
The BiP cochaperone ERdj4 removes misfolded proteins from the ER lumen by associating with ERAD machinery. Global deficiency of ERdj4 results in widespread constitutive ER stress, decreased survival, and metabolic derangements in mice. These findings indicate that the chaperone activity of ERdj4 is important for ER homeostasis in vivo. Endoplasmic reticulum–localized DnaJ 4 (ERdj4) is an immunoglobulin-binding protein (BiP) cochaperone and component of the endoplasmic reticulum–associated degradation (ERAD) pathway that functions to remove unfolded/misfolded substrates from the ER lumen under conditions of ER stress. To elucidate the function of ERdj4 in vivo, we disrupted the ERdj4 locus using gene trap (GT) mutagenesis, leading to hypomorphic expression of ERdj4 in mice homozygous for the trapped allele (ERdj4GT/GT). Approximately half of ERdj4GT/GT mice died perinatally associated with fetal growth restriction, reduced hepatic glycogen stores, and hypoglycemia. Surviving adult mice exhibited evidence of constitutive ER stress in multiple cells/tissues, including fibroblasts, lung, kidney, salivary gland, and pancreas. Elevated ER stress in pancreatic β cells of ERdj4GT/GT mice was associated with β cell loss, hypoinsulinemia, and glucose intolerance. Collectively these results suggest an important role for ERdj4 in maintaining ER homeostasis during normal fetal growth and postnatal adaptation to metabolic stress.