Distinct proteostasis states drive pharmacologic chaperone susceptibility for cystic fibrosis transmembrane conductance regulator misfolding mutants.
Distinct proteostasis states drive pharmacologic chaperone susceptibility for cystic fibrosis transmembrane conductance regulator misfolding mutants.
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DOI：
10.1091/mbc.e21-11-0578
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发表时间：
2022-06-01
影响因子：
3.3
通讯作者：
Plate, Lars
中科院分区：
文献类型：
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作者：
McDonald, Eli Fritz;Sabusap, Carleen Mae P.;Kim, Minsoo;Plate, Lars
药理学分子伴侣代表一类用于治疗蛋白质错误折叠疾病的治疗性化合物。最突出的例子之一是FDA批准的药理学伴侣Lumacaftor（VX-809），它改变了囊性纤维化（CF）治疗。CF是由CF跨膜传导调节因子（CFTR）突变引起的致命疾病。VX-809纠正F508 del CFTR的折叠，F508 del CFTR是最常见的患者突变，但F508 del仅表现出轻微的VX-809应答。相比之下，罕见突变P67 L和L206 W对VX-809高度反应，而G85 E则无反应。尽管VX-809在临床上取得了成功，但突变体不同易感性的机制起源仍不清楚。在这里，我们使用interactomics来表征VX-809对P67 L和L206 W的蛋白质抑制相互作用的影响，并将其与F508 del和G85 E进行比较。我们确定，与F508 del和G85 E相比，高反应突变P67 L和L206 W与蛋白酶体和自噬降解机制的相互作用降低。然后，我们显示抑制蛋白酶体减弱P67 L和L206 W VX-809反应。我们的数据表明，蛋白质降解VX-809纠正以前未确定的，但需要的作用。此外，我们提出了一种方法，用于确定药理学伴侣的特异性治疗反应的muscle的蛋白质稳定特性。
Pharmacological chaperones represent a class of therapeutic compounds for treating protein misfolding diseases. One of the most prominent examples is the FDA-approved pharmacological chaperone lumacaftor (VX-809), which has transformed cystic fibrosis (CF) therapy. CF is a fatal disease caused by mutations in the CF transmembrane conductance regulator (CFTR). VX-809 corrects folding of F508del CFTR, the most common patient mutation, yet F508del exhibits only mild VX-809 response. In contrast, rarer mutations P67L and L206W are hyperresponsive to VX-809, while G85E is nonresponsive. Despite the clinical success of VX-809, the mechanistic origin for the distinct susceptibility of mutants remains unclear. Here we use interactomics to characterize the impact of VX-809 on proteostasis interactions of P67L and L206W and compare these with F508del and G85E. We determine that hyperresponsive mutations P67L and L206W exhibit decreased interactions with proteasomal and autophagy degradation machinery compared with F508del and G85E. We then show inhibiting the proteasome attenuates P67L and L206W VX-809 response. Our data suggest a previously unidentified but required role for protein degradation in VX-809 correction. Furthermore, we present an approach for identifying proteostasis characteristics of mutant-specific therapeutic response to pharmacological chaperones.