ERdj4 and ERdj5 are required for endoplasmic reticulum-associated protein degradation of misfolded surfactant protein C
ERdj4 and ERdj5 are required for endoplasmic reticulum-associated protein degradation of misfolded surfactant protein C
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DOI：
10.1091/mbc.e07-07-0674
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发表时间：
2008-06-01
影响因子：
3.3
通讯作者：
Weaver, Timothy E.
中科院分区：
文献类型：
--
作者：
Dong, Mei;Bridges, James P.;Weaver, Timothy E.
与人类患者间质性肺病相关的SFTPC基因突变导致编码的表面活性蛋白C（SP-C）前蛋白的错误折叠、内质网（ER）滞留和降解。在这项研究中，基因特异性诱导的两种疾病相关突变的瞬时表达的微阵列分析确定。免疫球蛋白重链结合蛋白（BiP）和两个热休克蛋白40家族成员，内质网定位的DnaJ同源物ERdj 4和ERdj 5，显着升高，并表现出长期和特定的关联与错误折叠的前蛋白;相反，ERdj 3与BiP相互作用，但它不与野生型或突变型SP-C。错误折叠的SP-C，ERdj 4和ERdj 5与p97/VCP共沉淀，表明辅伴侣蛋白保持与错误折叠的前蛋白结合，直到其移位到胞质溶胶。ERdj 4和ERdj 5表达的敲低增加了ER保留并抑制了错误折叠的SP-C的降解，但对野生型蛋白的影响不大。ERdj 4和ERdj 5在X-box结合蛋白1（-/-）小鼠胚胎成纤维细胞中的瞬时表达基本上恢复了突变SP-C前蛋白的快速降解，而HPD突变体的转染未能拯救SP-C内质网相关蛋白的降解。ERdj 4和ERdj 5促进错误折叠的SP-C的周转，并且这种活性依赖于它们刺激BiP ATP酶活性的能力。
Mutations in the SFTPC gene associated with interstitial lung disease in human patients result in misfolding, endoplasmic reticulum (ER) retention, and degradation of the encoded surfactant protein C (SP-C) proprotein. In this study, genes specifically induced in response to transient expression of two disease-associated mutations were identified by microarray analyses. Immunoglobulin heavy chain binding protein (BiP) and two heat shock protein 40 family members, endoplasmic reticulum-localized DnaJ homologues ERdj4 and ERdj5, were significantly elevated and exhibited prolonged and specific association with the misfolded proprotein; in contrast, ERdj3 interacted with BiP, but it did not associate with either wild-type or mutant SP-C. Misfolded SP-C, ERdj4, and ERdj5 coprecipitated with p97/VCP indicating that the cochaperones remain associated with the misfolded proprotein until it is dislocated to the cytosol. Knockdown of ERdj4 and ERdj5 expression increased ER retention and inhibited degradation of misfolded SP-C, but it had little effect on the wild-type protein. Transient expression of ERdj4 and ERdj5 in X-box binding protein 1(-/-) mouse embryonic fibroblasts substantially restored rapid degradation of mutant SP-C proprotein, whereas transfection of HPD mutants failed to rescue SP-C endoplasmic reticulum-associated protein degradation. ERdj4 and ERdj5 promote turnover of misfolded SP-C and this activity is dependent on their ability to stimulate BiP ATPase activity.