4-Phenylbutyric acid treatment rescues trafficking and processing of a mutant surfactant protein-C.
4-Phenylbutyric acid treatment rescues trafficking and processing of a mutant surfactant protein-C.
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4-苯基丁酸处理可挽救突变型表面活性剂蛋白-C 的运输和加工。
DOI：
10.1165/rcmb.2012-0003oc
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发表时间：
2012
影响因子：
6.4
通讯作者：
Weaver,TimothyE
中科院分区：
文献类型：
--
作者：
Stewart,GarethA;Ridsdale,Ross;Martin,EmilyP;Na,Cheng-Lun;Xu,Yan;Mandapaka,Karunyakanth;Weaver,TimothyE
编码表面活性蛋白-C（SP-C）的SFTPC基因突变与间质性肺病（ILD）相关。突变体SP-C的细胞内命运的知识是必不可少的治疗设计，以纠正运输/加工的前蛋白，并防止细胞毒性聚集体的形成。我们评估了化学伴侣纠正三种疾病相关突变SP-C蛋白的运输和加工的潜力。用野生型（SP-CWT）或突变型（SP-CL188 Q、SP-C Δ外显子4或SP-CI73 T）SP-C稳定转染HEK293细胞，并鉴定具有相似SP-C mRNA表达的细胞系。评估了化学伴侣4-苯基丁酸（PBA）和亲溶酶体药物对胞内转运至内溶酶体途径以及随后SP-C前蛋白转化为成熟肽的影响。尽管SP-C mRNA表达相当，但前蛋白浓度差异很大：SP-CI 73 T比SP-CWT更丰富，并且定位于细胞表面，而SP-C Δ exon 4几乎检测不到。相反，SP-CL188Q和SP-CWTproprotein浓度相当，少量SP-CL188Q定位于内溶酶体途径。PBA处理恢复了SP-CL188Q向SP-CWTconcentration的运输和加工，但不能纠正SP-CI73T的误转录或拯救SP-C Δ exon4。PBA处理还促进SP-C前体蛋白的聚集，包括SP-CL188Q。这项研究提供了一个化学伴侣可以纠正疾病相关的突变SP-C前蛋白的错误反应和加工的原则的证据。
Mutations in theSFTPCgene, encoding surfactant protein–C (SP-C), are associated with interstitial lung disease (ILD). Knowledge of the intracellular fate of mutant SP-C is essential in the design of therapies to correct trafficking/processing of the proprotein, and to prevent the formation of cytotoxic aggregates. We assessed the potential of a chemical chaperone to correct the trafficking and processing of three disease-associated mutant SP-C proteins. HEK293 cells were stably transfected with wild-type (SP-CWT) or mutant (SP-CL188Q, SP-CΔexon4, or SP-CI73T) SP-C, and cell lines with a similar expression of SP-C mRNA were identified. The effects of the chemical chaperone 4-phenylbutyric acid (PBA) and lysosomotropic drugs on intracellular trafficking to the endolysosomal pathway and the subsequent conversion of SP-C proprotein to mature peptide were assessed. Despite comparable SP-C mRNA expression, proprotein concentrations varied greatly: SP-CI73Twas more abundant than SP-CWTand was localized to the cell surface, whereas SP-CΔexon4was barely detectable. In contrast, SP-CL188Qand SP-CWTproprotein concentrations were comparable, and a small amount of SP-CL188Qwas localized to the endolysosomal pathway. PBA treatment restored the trafficking and processing of SP-CL188Qto SP-CWTconcentrations, but did not correct the mistrafficking of SP-CI73Tor rescue SP-CΔexon4. PBA treatment also promoted the aggregation of SP-C proproteins, including SP-CL188Q. This study provides proof of the principle that a chemical chaperone can correct the mistrafficking and processing of a disease-associated mutant SP-C proprotein.
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DOI：
10.1152/ajpcell.2000.278.2.c259
发表时间：
2000-02-01
影响因子：
5.5
作者：
Rubenstein, RC;Zeitlin, PL
通讯作者：
Zeitlin, PL
影响因子：
3.3
作者：
Dong, Mei;Bridges, James P.;Weaver, Timothy E.
通讯作者：
Weaver, Timothy E.
DOI：
10.1165/rcmb.2005-0009oc
发表时间：
2005-06-01
影响因子：
6.4
作者：
Mulugeta, S;Nguyen, V;Beers, MF
通讯作者：
Beers, MF
DOI：
10.1164/rccm.200112-123oc
发表时间：
2002-05-01
影响因子：
24.7
作者：
Thomas, AQ;Lane, K;Loyd, JE
通讯作者：
Loyd, JE
影响因子：
20.3
作者：
COLLINS, AF;PEARSON, HA;DOVER, GJ
通讯作者：
DOVER, GJ