Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C.
Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C.
复制标题
适应和增加与错误折叠SP-C的本构表达相关的感染的敏感性。
DOI：
10.1083/jcb.200508016
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发表时间：
2006-01-30
影响因子：
7.8
通讯作者：
Weaver, Timothy E
中科院分区：
文献类型：
--
作者：
Bridges, James P;Xu, Yan;Na, Cheng-Lun;Wong, Hector R;Weaver, Timothy E
编码SP-C（表面活性蛋白C; SFTPC）的基因突变与儿童和成人间质性肺病（ILD）有关。在转基因小鼠的瞬时转染细胞和II型细胞中，索引突变SP-CΔ exon 4的表达导致前蛋白的错误折叠、内质网（ER）应激途径的激活和细胞毒性。在这项研究中，我们发现稳定转染的细胞通过NF-κ B依赖的途径适应由SP-CΔ exon 4组成性表达所施加的慢性ER应激。然而，用呼吸道合胞病毒感染表达SP-CΔ外显子4的细胞，导致与突变体前蛋白积累相关的细胞毒性显著增强，未折叠蛋白反应的显著激活和细胞死亡。对错误折叠的SP-C施加的慢性ER应激的适应与对病毒诱导的细胞死亡的易感性增加有关。SFTPC突变患者ILD发病年龄的广泛变异性可能与最终压倒稳态细胞保护反应的环境损伤有关。
Mutations in the gene encoding SP-C (surfactant protein C; SFTPC) have been linked to interstitial lung disease (ILD) in children and adults. Expression of the index mutation, SP-CΔexon4, in transiently transfected cells and type II cells of transgenic mice resulted in misfolding of the proprotein, activation of endoplasmic reticulum (ER) stress pathways, and cytotoxicity. In this study, we show that stably transfected cells adapted to chronic ER stress imposed by the constitutive expression of SP-CΔexon4 via an NF-κB–dependent pathway. However, the infection of cells expressing SP-CΔexon4 with respiratory syncytial virus resulted in significantly enhanced cytotoxicity associated with accumulation of the mutant proprotein, pronounced activation of the unfolded protein response, and cell death. Adaptation to chronic ER stress imposed by misfolded SP-C was associated with increased susceptibility to viral-induced cell death. The wide variability in the age of onset of ILD in patients with SFTPC mutations may be related to environmental insults that ultimately overwhelm the homeostatic cytoprotective response.