Misfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase-4- and cytochrome c-related mechanisms
Misfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase-4- and cytochrome c-related mechanisms
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DOI：
10.1152/ajplung.00025.2007
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发表时间：
2007-09-01
影响因子：
4.9
通讯作者：
Beers, Michael F.
中科院分区：
文献类型：
--
作者：
Mulugeta, Surafel;Maguire, Jean Ann;Beers, Michael F.
表面活性剂蛋白C （SP-C）的BRICHOS结构域内的一些突变与间质性肺疾病有关。最近的研究表明，这些突变引起蛋白质的错误折叠，从而启动未折叠蛋白反应来解决不正确的折叠或促进蛋白质降解。我们已经报道了其中一种蛋白，外显子4缺失突变（hSP-C-Delta外显子4）的体外表达会引起内质网（ER）应激，抑制蛋白酶体功能，并激活caspase-3介导的细胞凋亡。为了进一步阐明细胞功能障碍的机制和常见途径，在肺上皮源性A549和肾上皮源性（HEK-293） GFPu-1细胞系中，通过瞬时表达两种SP-C BRICHOS结构域突变体（BRISPC）蛋白（hSP-C-Delta外显子4、hSP-C-L188Q）和控制蛋白，进行了各种检测。与对照组相比，表达任何一种BRICHOS突变蛋白的细胞一致表现出不溶性聚集体的形成增加，X-box结合蛋白1 （XBP-1）的肌醇依赖酶1剪接的促进增强，蛋白酶体活性的显著抑制，线粒体细胞色素c释放的诱导增强，caspase-4和caspase-3的激活增加，导致细胞凋亡。这些结果提示了常见的细胞反应，包括细胞死亡信号通路的启动，这些肺部疾病相关的BRISPC蛋白。
Several mutations within the BRICHOS domain of surfactant protein C (SP-C) have been linked to interstitial lung disease. Recent studies have suggested that these mutations cause misfolding of the proprotein (proSP-C), which initiates the unfolded protein response to resolve improper folding or promote protein degradation. We have reported that in vitro expression of one of these proteins, the exon 4 deletion mutant (hSP-C-Delta exon4), causes endoplasmic reticulum (ER) stress, inhibits proteasome function, and activates caspase-3-mediated apoptosis. To further elucidate mechanisms and common pathways for cellular dysfunction, various assays were performed by transiently expressing two SP-C BRICHOS domain mutant (BRISPC) proteins (hSP-C-Delta exon4, hSP-C-L188Q) and control proteins in lung epithelium-derived A549 and kidney epithelium-derived (HEK-293) GFPu-1 cell lines. Compared with controls, cells expressing either BRICHOS mutant protein consistently exhibited increased formation of insoluble aggregates, enhanced promotion of inositol-requiring enzyme 1-dependent splicing of X-box binding protein-1 (XBP-1), significant inhibition of proteasome activity, enhanced induction of mitochondrial cytochrome c release, and increased activations of caspase-4 and caspase-3, leading to apoptosis. These results suggest common cellular responses, including initiation of cell-death signaling pathways, to these lung disease-associated BRISPC proteins.