Aberrant quality control in the endoplasmic reticulum impairs the biosynthesis of pulmonary surfactant in mice expressing mutant BiP
Aberrant quality control in the endoplasmic reticulum impairs the biosynthesis of pulmonary surfactant in mice expressing mutant BiP
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DOI：
10.1038/sj.cdd.4402151
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发表时间：
2007-08-01
影响因子：
12.4
通讯作者：
Aoe, T.
中科院分区：
文献类型：
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作者：
Mimura, N.;Hamada, H.;Aoe, T.
内质网（ER）中错误折叠蛋白的积累可诱导未折叠蛋白反应（UPR），从而减轻分泌途径中的蛋白质过载。虽然UPR在多种病理条件下被激活，但其在发育和成年期的生理作用尚未完全阐明。结合免疫球蛋白蛋白（BiP）是一种内质网伴侣，是内质网功能的核心。我们制造了敲入小鼠，表达缺乏检索序列的突变BiP，导致内质网功能缺陷，但没有完全消除BiP。在胚胎成纤维细胞中，UPR补偿了BiP的突变。然而，表达突变BiP的新生儿由于肺泡II型上皮细胞分泌肺表面活性物质受损而发生呼吸衰竭。表面活性剂蛋白(SP)-C表达降低，片状体畸形，提示BiP在肺表面活性剂生物合成中起关键作用。由于肺表面活性物质在分泌途径中需要广泛的翻译后加工，这些研究结果表明，在分泌细胞（如肺泡II型细胞）中，UPR对于管理发育过程中发生的正常生理内质网蛋白过载至关重要。此外，这种适应性机制的失败可能会增加肺对环境损伤的易感性，如缺氧和缺血，最终导致新生儿呼吸衰竭。
Accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces the unfolded protein response (UPR), which alleviates protein overload in the secretory pathway. Although the UPR is activated under diverse pathological conditions, its physiological role during development and in adulthood has not been fully elucidated. Binding immunoglobulin protein (BiP) is an ER chaperone, which is central to ER function. We produced knock- in mice expressing a mutant BiP lacking the retrieval sequence to cause a defect in ER function without completely eliminating BiP. In embryonic fibroblasts, the UPR compensated for mutation of BiP. However, neonates expressing mutant BiP suffered respiratory failure due to impaired secretion of pulmonary surfactant by alveolar type II epithelial cells. Expression of surfactant protein (SP)-C was reduced and the lamellar body was malformed, indicating that BiP plays a critical role in the biosynthesis of pulmonary surfactant. Because pulmonary surfactant requires extensive post-translational processing in the secretory pathway, these findings suggest that in secretory cells, such as alveolar type II cells, the UPR is essential for managing the normal physiological ER protein overload that occurs during development. Moreover, failure of this adaptive mechanism may increase pulmonary susceptibility to environmental insults, such as hypoxia and ischemia, ultimately leading to neonatal respiratory failure.