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Targeting autophagy as a novel strategy for facilitating the therapeutic action of potentiators on ΔF508 cystic fibrosis transmembrane conductance regulator

机译:靶向自噬是促进增效剂对ΔF508囊性纤维化跨膜电导调节剂的治疗作用的新策略

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textabstractChannel activators (potentiators) of cystic fibrosis (CF) transmembrane conductance regulator (CFTR), can be used for the treatment of the small subset of CF patients that carry plasma membrane-resident CFTR mutants. However, approximately 90% of CF patients carry the misfolded ΔF508-CFTR and are poorly responsive to potentiators, because ΔF508-CFTR is intrinsically unstable at the plasma membrane (PM) even if rescued by pharmacological correctors. We have demonstrated that human and mouse CF airways are autophagy deficient due to functional sequestration of BEC N1 and that the tissue transglutaminase-2 inhibitor, cystamine, or antioxidants restore BEC N1-dependent autophagy and reduce SQSTM1/p62 levels, thus favoring ΔF508-CFTR trafficking to the epithelial surface. Here, we investigated whether these treatments could facilitate the beneficial action of potentiators on ΔF508-CFTR homozygous airways. Cystamine or the superoxide dismutase (SO D)/catalase-mimetic EUK-134 stabilized ΔF508-CFTR at the plasma membrane of airway epithelial cells and sustained the expression of CFTR at the epithelial surface well beyond drug withdrawal, overexpressing BECN1 and depleting SQSTM1. This facilitates the beneficial action of potentiators in controlling inflammation in ex vivo ΔF508-CFTR homozygous human nasal biopsies and in vivo in mouse ΔF508-CFTR lungs. Direct depletion of Sqstm1 by shRNAs in vivo in ΔF508-CFTR mice synergized with potentiators in sustaining surface CFTR expression and suppressing inflammation. Cystamine pre-treatment restored ΔF508-CFTR response to the CFTR potentiators genistein, Vrx-532 or Vrx-770 in freshly isolated brushed nasal epithelial cells from ΔF508-CFTR homozygous patients. These findings delineate a novel therapeutic strategy for the treatment of CF patients with the ΔF508-CFTR mutation in which patients are first treated with cystamine and subsequently pulsed with CFTR potentiators.
机译:textabstract囊性纤维化(CF)跨膜电导调节剂(CFTR)的通道激活剂(增强剂)可用于治疗携带血浆膜驻留CFTR突变体的CF患者的一小部分。但是,大约90%的CF患者携带错误折叠的ΔF508-CFTR,并且对增强剂的反应较差,因为即使通过药理校正剂拯救,ΔF508-CFTR在质膜(PM)上本质上也是不稳定的。我们已经证明,人和小鼠CF气道由于BEC N1的功能隔离而自噬不足,并且组织转谷氨酰胺酶2抑制剂,胱胺或抗氧化剂可恢复BEC N1依赖性自噬并降低SQSTM1 / p62水平,因此有利于ΔF508-CFTR转运到上皮表面。在这里,我们调查了这些处理是否可以促进增效剂对ΔF508-CFTR纯合气道的有益作用。半胱胺或超氧化物歧化酶(SO D)/过氧化氢酶类似物EUK-134使气道上皮细胞质膜上的ΔF508-CFTR稳定,并在上皮表面维持CFTR的表达,而不仅是药物停药,过表达BECN1和耗竭SQSTM1。这促进了增强剂在控制离体ΔF508-CFTR纯合人鼻活检和小鼠ΔF508-CFTR肺体内炎症中的有益作用。在增强表面CFTR表达和抑制炎症反应的增效剂增效的ΔF508-CFTR小鼠体内,shRNA在体内直接消耗Sqstm1。半胱胺预处理在来自ΔF508-CFTR纯合患者的新鲜分离的刷鼻上皮细胞中恢复了对CFTR增强剂染料木黄酮,Vrx-532或Vrx-770的ΔF508-CFTR反应。这些发现勾画出了一种治疗具有ΔF508-CFTR突变的CF患者的新颖治疗策略,该方法首先用胱胺治疗患者,然后用CFTR增强剂脉冲治疗。

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