Evidence for alteration of calpain/calpastatin system in PBMC of cystic fibrosis patients
Evidence for alteration of calpain/calpastatin system in PBMC of cystic fibrosis patients
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DOI：
10.1016/j.bbadis.2011.09.013
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发表时间：
2011-12-01
影响因子：
6.2
通讯作者：
Melloni, Edon
中科院分区：
文献类型：
--
作者：
Averna, Monica;Stifanese, Roberto;Melloni, Edon
我们在此报道，在F508del-CFTR纯合子患者的外周血单个核细胞（PBMC）中，钙蛋白酶和钙pastatin系统发生了深刻的改变。事实上，在对照PBMC中几乎无法检测到的calpain基础活性，在囊性纤维化（CF）患者的细胞中可以显著测量到，这也是由于calpastatin蛋白和抑制活性都降低了40-60%。CF患者细胞中的组成型蛋白酶激活诱导突变的囊性纤维化跨膜传导调节因子（CFTR）在100 kD + 70 kD分裂形式中大量积累，以及与CFTR复合物相关的蛋白质降解。具体来说，支架蛋白Na+/H+交换器3调节因子-1 （NHERF-1）被转化为两个不同的片段，质量分别为35 kD和20 kD，但后者是最具代表性的片段，从而表明CF-PBMC中CFTR复合物经历了很大的分解。总之，我们的观察结果为钙蛋白酶在调节质膜离子电导中的作用提供了新的信息，并为这种蛋白酶活性从生理功能向病理功能的转变提供了额外的证据。(C) 2011 Elsevier B.V.版权所有
We are here reporting that in peripheral blood mononuclear cells (PBMC) of patients homozygous for F508del-CFTR the calpain calpastatin system undergoes a profound alteration. In fact, calpain basal activity, almost undetectable in control PBMC, becomes measurable at a significant extent in cells from cystic fibrosis (CF) patients, also due to a 40-60% decrease in both calpastatin protein and inhibitory activity. Constitutive protease activation in CF patients' cells induces a large accumulation of the mutated cystic fibrosis transmembrane conductance regulator (CFTR) in the 100 kD + 70 kD split forms as well as a degradation of proteins associated to the CFTR complex. Specifically, the scaffolding protein Na+/H+ exchanger 3 regulatory factor-1 (NHERF-1) is converted in two distinct fragments showing masses of 35 kD and 20 kD, being however the latter form the most represented one, thereby indicating that in CF-PBMC the CFTR complex undergoes a large disorganization. In conclusion, our observations are providing new information on the role of calpain in the regulation of plasma membrane ion conductance and provide additional evidence on the transition of this protease activity from a physiological to a pathological function. (C) 2011 Elsevier B.V. All rights reserved.