Targeting the Intracellular Environment in Cystic Fibrosis: Restoring Autophagy as a Novel Strategy to Circumvent the CFTR Defect.
Targeting the Intracellular Environment in Cystic Fibrosis: Restoring Autophagy as a Novel Strategy to Circumvent the CFTR Defect.
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DOI：
10.3389/fphar.2013.00001
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发表时间：
2013
影响因子：
5.6
通讯作者：
Maiuri L
中科院分区：
文献类型：
--
作者：
Villella VR;Esposito S;Bruscia EM;Maiuri MC;Raia V;Kroemer G;Maiuri L
囊性纤维化（CF）患者携带最常见的CF跨膜电导调节因子（CFTR） F508del缺失突变，对CFTR通道活性增强剂反应较差，CFTR通道活性增强剂可用于治疗遗传携带质膜（PM）驻留CFTR突变的一小部分CF患者。错误折叠的F508del-CFTR蛋白在PM中是不稳定的，即使被阻止其在细胞内保留和降解的药物拯救。CF是一种构象性疾病，其中CFTR缺陷引起自噬功能障碍导致一般蛋白酶平衡的显著紊乱。在这篇综述中，我们讨论了拯救Beclin 1 (BECN1)，一个自噬体形成的主要参与者，如何通过直接的基因转移或间接的给药蛋白抑制调节因子，来稳定f508dl - cftr。我们重点研究了F508del-CFTR纯合子支气管上皮或小鼠肺中外周蛋白平衡的改善与CFTR PM稳定性的关系。此外，本文回顾了最近的临床前证据，表明靶向错误折叠突变体CFTR周围的细胞内环境而不是蛋白质本身可能是一种有吸引力的治疗选择，可以使携带F508del-CFTR突变的患者对CFTR增强剂对肺部炎症的有益作用敏感。
Cystic fibrosis (CF) patients harboring the most common deletion mutation of the CF transmembrane conductance regulator (CFTR), F508del, are poor responders to potentiators of CFTR channel activity which can be used to treat a small subset of CF patients who genetically carry plasma membrane (PM)-resident CFTR mutants. The misfolded F508del-CFTR protein is unstable in the PM even if rescued by pharmacological agents that prevent its intracellular retention and degradation. CF is a conformational disease in which defective CFTR induces an impressive derangement of general proteostasis resulting from disabled autophagy. In this review, we discuss how rescuing Beclin 1 (BECN1), a major player of autophagosome formation, either by means of direct gene transfer or indirectly by administration of proteostasis regulators, could stabilize F508del-CFTR at the PM. We focus on the relationship between the improvement of peripheral proteostasis and CFTR PM stability in F508del-CFTR homozygous bronchial epithelia or mouse lungs. Moreover, this article reviews recent pre-clinical evidence indicating that targeting the intracellular environment surrounding the misfolded mutant CFTR instead of protein itself could constitute an attractive therapeutic option to sensitize patients carrying the F508del-CFTR mutation to the beneficial action of CFTR potentiators on lung inflammation.
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影响因子：
16
作者：
Duran A;Amanchy R;Linares JF;Joshi J;Abu-Baker S;Porollo A;Hansen M;Moscat J;Diaz-Meco MT
通讯作者：
Diaz-Meco MT
影响因子：
4.8
作者：
Antonyak, MA;Miller, AM;Cerione, RA
通讯作者：
Cerione, RA
影响因子：
56.9
作者：
Egan, ME;Pearson, M;Caplan, MJ
通讯作者：
Caplan, MJ
DOI：
10.1165/rcmb.2009-0347oc
发表时间：
2011-01-01
影响因子：
6.4
作者：
Antigny, Fabrice;Norez, Caroline;Vandebrouck, Clarisse
通讯作者：
Vandebrouck, Clarisse
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje