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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mutant surfactant A2 proteins associated with familial pulmonary fibrosis and lung cancer induce TGF-β1 secretion
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Mutant surfactant A2 proteins associated with familial pulmonary fibrosis and lung cancer induce TGF-β1 secretion

机译：与家族性肺纤维化和肺癌相关的突变型表面活性剂A2蛋白诱导TGF-β1分泌

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摘要

Mutations in the genes encoding the lung surfactant proteins are found in patients with interstitial lung disease and lung cancer, but their, pathologic mechanism is poorly understood. Here we show that bronchoalveolar lavage fluid from humans heterozygous for a missense mutation in the gene encoding surfactant protein (SP)-A2 (SFTPA2) contains more TGF-β1 than control samples. Expression of mutant SP-A2 in lung epithelial cells leads to secretion of latent TGF-β1, which is capable of autocrine and para-crine signaling. TGF-β1 secretion is not observed in lung epithelial cells expressing the common 5P-A2 variants or other misfolded proteins capable of increasing cellular endoplasmic reticulum stress. Activation of the unfolded protein response is necessary for maximal TGF-β1 secretion because gene silencing of the unfolded protein response transducers leads to an ~50% decrease in mutant SP-A2-mediated TGF-β1 secretion. Expression of the mutant SP-A2 proteins leads to the coordinated increase in gene expression of TGF-β1 and two TGF-β1-binding proteins, LTBP-1 and LTBP-4; expression of the latter is necessary for secretion of this cytokine. Inhibition of the TGF-β autocrine positive feedback loop by a pan-TGF-β-neutralizing antibody, a TGF-β receptor antagonist, or LTBP gene silencing results in the reversal of TGF-β-mediated epithelial-to-mesenchymal transition and cell death. Because secretion of latent TGF-β1 is induced specifically by mutant SP-A2 proteins, therapeutics targeted to block this pathway may be especially beneficial for this molecularly defined subgroup of patients.
机译：在患有间质性肺病和肺癌的患者中发现了编码肺表面活性剂蛋白的基因突变，但对其病理机制了解甚少。在这里，我们显示，来自人类杂合子的支气管肺泡灌洗液在编码表面活性剂蛋白（SP）-A2（SFTPA2）的基因中发生错义突变，比对照样品含有更多的TGF-β1。肺上皮细胞中突变SP-A2的表达导致潜在TGF-β1的分泌，该TGF-β1能够自分泌和旁分泌信号传导。在表达常见的5P-A2变异体或其他能够增加细胞内质网应激的错误折叠蛋白的肺上皮细胞中未观察到TGF-β1分泌。未折叠的蛋白质应答的激活对于最大的TGF-β1分泌是必需的，因为未折叠的蛋白质应答传感器的基因沉默会导致突变体SP-A2介导的TGF-β1分泌降低约50％。突变的SP-A2蛋白的表达导致TGF-β1和两个TGF-β1结合蛋白LTBP-1和LTBP-4的基因表达协同增加。后者的表达对于分泌这种细胞因子是必需的。泛TGF-β中和抗体，TGF-β受体拮抗剂或LTBP基因沉默抑制TGF-β自分泌正反馈回路会导致TGF-β介导的上皮-间充质转化和细胞逆转死亡。由于潜在的TGF-β1的分泌是由突变SP-A2蛋白特异性诱导的，因此靶向阻断该途径的治疗药物可能对该患者的分子定义亚群特别有益。

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  • 作者

    Meenakshi Maitra; Christopher A. Cano; Christine Kim Garcia;

  • 作者单位

    Eugene McDermott Center for Human Growth and Development University of Texas Southwestern Medical Center, Dallas, TX 75229;

    Eugene McDermott Center for Human Growth and Development University of Texas Southwestern Medical Center, Dallas, TX 75229;

    Eugene McDermott Center for Human Growth and Development University of Texas Southwestern Medical Center, Dallas, TX 75229,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75229;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    genetics; idiopathic pulmonary fibrosis; IPF;

    机译：遗传学特发性肺纤维化IPF;

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