XBP1S Regulates MUC5B in a Promoter Variant-Dependent Pathway in Idiopathic Pulmonary Fibrosis Airway Epithelia
XBP1S Regulates MUC5B in a Promoter Variant-Dependent Pathway in Idiopathic Pulmonary Fibrosis Airway Epithelia
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DOI：
10.1164/rccm.201810-1972oc
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发表时间：
2019-07-15
影响因子：
24.7
通讯作者：
Boucher, Richard C.
中科院分区：
文献类型：
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作者：
Chen, Gang;Ribeiro, Carla M. P.;Boucher, Richard C.
基本原理：目的是将特发性肺纤维化（IPF）发病机制的要素联系起来，包括与损伤/炎症和重塑相关的呼吸道上皮中的慢性内质网应激、远端气道粘液阻塞和蜂窝状囊肿形成与MUC 5 B蓄积（粘蛋白5 B），以及IPF风险与MUC 5 B启动子多态性之间的相关性。为了测试内质网（ER）应激传感器蛋白ERN 2是否（ER-到-核信号传导2）及其下游效应物，剪接形式的XBP 1 S（X-box-binding protein 1），调节MUC 5 B表达并差异性激活呼吸道上皮中的MUC 5 B启动子变体。使用原代人气道上皮（HAE）细胞、转基因小鼠模型、人IPF肺组织和表达XBP 1 S和MUC 5 B启动子的细胞系来探索ERN 2/XBP 1 S途径与MUC 5 B之间的关系。在HAE细胞中使用该途径的抑制剂KIRA 6和XBP 1 CRISPR-Cas9以探索治疗潜力。测量和主要结果：ERN 2调节MUC 5 B和MUC 5AC mRNA。下游XBP 1 S选择性地促进MUC 5 B在体外和在体内远端鼠气道上皮中的表达。在MUC 5 B启动子rs35705950变异体的情况下，XBP 1 S结合到MUC 5 B启动子的近端区域并差异上调MUC 5 B表达。高水平的ERN 2和XBP 1 S与人IPF肺远端气道中过量的MUC 5 B mRNA相关。KIRA 6和XBP 1 CRISPR-Cas9可抑制HAE细胞中细胞因子诱导的MUC 5 B表达。结论：IPF中MUC 5 B主导的粘液阻塞是由正反馈MUCERN 2-XBP 1 S通路调节的，提供了一种将MUC 5 B启动子rs35705950多态性与IPF发病机制联系起来的未折叠蛋白反应依赖性机制。抑制ERN 2依赖性通路/元件可能为IPF提供一种治疗选择。
Rationale: The goal was to connect elements of idiopathic pulmonary fibrosis (IPF) pathogenesis, including chronic endoplasmic reticulum stress in respiratory epithelia associated with injury/inflammation and remodeling, distal airway mucus obstruction and honeycomb cyst formation with accumulation of MUC5B (mucin 5B), and associations between IPF risk and polymorphisms in the MUC5B promoter.Objectives: To test whether the endoplasmic reticulum (ER) stress sensor protein ERN2 (ER-to-nucleus signaling 2) and its downstream effector, the spliced form of XBP1S (X-box-binding protein 1), regulate MUC5B expression and differentially activate the MUC5B promoter variant in respiratory epithelia.Methods: Primary human airway epithelial (HAE) cells, transgenic mouse models, human IPF lung tissues, and cell lines expressing XBP1S and MUC5B promoters were used to explore relationships between the ERN2/XBP1S pathway and MUC5B. An inhibitor of the pathway, KIRA6, and XBP1 CRISPR-Cas9 were used in HAE cells to explore therapeutic potential.Measurements and Main Results: ERN2 regulated MUC5B and MUC5AC mRNAs. Downstream XBP1S selectively promoted MUC5B expression in vitro and in distal murine airway epithelia in vivo. XBP1S bound to the proximal region of the MUC5B promoter and differentially upregulated MUC5B expression in the context of the MUC5B promoter rs35705950 variant. High levels of ERN2 and XBP1S were associated with excessive MUC5B mRNAs in distal airways of human IPF lungs. Cytokine-induced MUC5B expression in HAE cells was inhibited by KIRA6 and XBP1 CRISPR-Cas9.Conclusions: A positive feedback bistable ERN2-XBP1S pathway regulates MUC5B-dominated mucus obstruction in IPF, providing an unfolded protein response-dependent mechanism linking the MUC5B promoter rs35705950 polymorphism with IPF pathogenesis. Inhibiting ERN2-dependent pathways/elements may provide a therapeutic option for IPF.