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首页> 外文期刊>American Journal of Physiology >Misfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase-4- and cytochrome c-related mechanisms.
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Misfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase-4- and cytochrome c-related mechanisms.

机译：错误折叠的BRICHOS SP-C突变蛋白通过caspase-4-和细胞色素c相关机制诱导凋亡。

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摘要

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(Deltaexon4)), 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(Deltaexon4), hSP-C(L188Q)) and control proteins in lung epithelium-derived A549 and kidney epithelium-derived (HEK-293) GFP(u)-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.
机译：表面活性剂蛋白C（SP-C）的BRICHOS域内的几个突变与间质性肺疾病有关。最近的研究表明，这些突变会导致原蛋白（proSP-C）的错误折叠，从而引发未折叠的蛋白反应，以解决不正确的折叠或促进蛋白降解。我们已经报道这些蛋白质之一，外显子4缺失突变体（hSP-C（Deltaexon4））的体外表达，引起内质网（ER）压力，抑制蛋白酶体功能，并激活caspase-3介导的凋亡。为了进一步阐明细胞功能障碍的机制和常见途径，通过在肺上皮中瞬时表达两种SP-C BRICHOS域突变体（BRISPC）蛋白（hSP-C（Deltaexon4），hSP-C（L188Q））和对照蛋白来进行各种测定来源的A549和肾上皮来源的（HEK-293）GFP（u）-1细胞系。与对照组相比，表达两种BRICHOS突变蛋白的细胞始终表现出增加的不溶性聚集体形成，增强了对需要肌醇的酶1依赖的X-box结合蛋白1（XBP-1）的剪接，显着抑制了蛋白酶体的活性，诱导线粒体细胞色素c释放，并增加caspase-4和caspase-3的激活，导致细胞凋亡。这些结果表明对这些与肺疾病相关的BRISPC蛋白的常见细胞应答，包括细胞死亡信号传导途径的启动。

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