Mutant surfactant A2 proteins associated with familial pulmonary fibrosis and lung cancer induce TGF-β1 secretion (Retracted article. See vol. 112, pg. E5222, 2015)
Mutant surfactant A2 proteins associated with familial pulmonary fibrosis and lung cancer induce TGF-β1 secretion (Retracted article. See vol. 112, pg. E5222, 2015)
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DOI：
10.1073/pnas.1217069110
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发表时间：
2012-12-18
影响因子：
11.1
通讯作者：
Garcia, Christine Kim
中科院分区：
文献类型：
--
作者：
Maitra, Meenakshi;Cano, Christopher A.;Garcia, Christine Kim
在间质性肺疾病和肺癌患者中发现了肺表面活性蛋白编码基因的突变，但其病理机制尚不清楚。在这里，我们表明，支气管肺泡灌洗液从人类杂合子的错义突变的基因编码表面活性蛋白（SP）-A2（SFTPA 2）含有更多的TGF-β 1比对照样品。突变SP-A2在肺上皮细胞中的表达导致潜在TGF-β 1的分泌，其能够自分泌和旁分泌信号传导。在表达常见SP-A2变体或其他能够增加细胞内质网应激的错误折叠蛋白质的肺上皮细胞中未观察到TGF-β 1分泌。未折叠蛋白应答的激活对于最大的TGF-β 1分泌是必需的，因为未折叠蛋白应答转导物的基因沉默导致突变SP-A2介导的TGF-β 1分泌减少约50%。突变SP-A2蛋白的表达导致TGF-β 1和两种TGF-β 1结合蛋白LTBP-1和LTBP-4的基因表达的协调增加;后者的表达对于该细胞因子的分泌是必需的。通过泛TGF-β中和抗体、TGF-β受体拮抗剂或LTBP基因沉默抑制TGF-β自分泌正反馈环导致TGF-β介导的上皮向间充质转化和细胞死亡的逆转。由于潜伏性TGF-β 1的分泌是由突变型SP-A2蛋白特异性诱导的，因此靶向阻断该途径的治疗可能对这种分子定义的患者亚组特别有益。
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-beta 1 than control samples. Expression of mutant SP-A2 in lung epithelial cells leads to secretion of latent TGF-beta 1, which is capable of autocrine and paracrine signaling. TGF-beta 1 secretion is not observed in lung epithelial cells expressing the common SP-A2 variants or other misfolded proteins capable of increasing cellular endoplasmic reticulum stress. Activation of the unfolded protein response is necessary for maximal TGF-beta 1 secretion because gene silencing of the unfolded protein response transducers leads to an similar to 50% decrease in mutant SP-A2-mediated TGF-beta 1 secretion. Expression of the mutant SP-A2 proteins leads to the coordinated increase in gene expression of TGF-beta 1 and two TGF-beta 1-binding proteins, LTBP-1 and LTBP-4; expression of the latter is necessary for secretion of this cytokine. Inhibition of the TGF-beta autocrine positive feedback loop by a pan-TGF-beta-neutralizing antibody, a TGF-beta receptor antagonist, or LTBP gene silencing results in the reversal of TGF-beta-mediated epithelial-to-mesenchymal transition and cell death. Because secretion of latent TGF-beta 1 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.