期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：33
页码：12300-12305
DOI：10.1073/pnas.0404764101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Carbonic anhydrase (CA) IV is a glycosylphosphotidylinositol-anchored enzyme highly expressed on the plasma face of microcapillaries and especially strongly expressed in the choriocapillaris of the human eye. In collaboration with scientists at the University of Cape Town (Rondebosch, South Africa), we recently showed that the R14W mutation in the signal sequence of CA IV, which they identified in patients with the retinitis pigmentosa (RP) 17 form of autosomal dominant RP, results in accumulation of unfolded protein in the endoplasmic reticulum (ER), leading to ER stress, the unfolded protein response, and apoptosis in a large fraction of transfected COS-7 cells expressing mutant, but not wild-type, CA IV. Here we present experiments showing that several well characterized CA inhibitors largely prevent the adverse effects of expressing R14W CA IV in transfected COS-7 cells. Specifically, CA inhibitors prevent the accelerated turnover of the mutant protein, the up-regulation of Ig-binding protein, double-stranded RNA-regulated protein kinase-like ER kinase, and CCAAT/enhancer-binding protein homologous protein (markers of the unfolded protein response and ER stress), the inhibition of production of other secretory proteins expressed from COS-7-transfecting plasmids, and the induction of apoptosis, all characteristics of transfected cells expressing R14W CA IV. Furthermore, treatment with 4-phenylbutyric acid, a nonspecific chemical chaperone used in other protein-folding disorders, also dramatically reduces the apoptosis-inducing effect of expressing R14W CA IV cDNA in transfected COS-7 cells. These experiments suggest a promising approach to treatment of RP17 that might delay the onset or possibly prevent this autosomal dominant form of RP.
关键词：protein-folding disease ; unfolded protein response ; endoplasmic reticulum-associated protein degradation ; signal sequence mutation
