Rescue of growth defects of yeast cdc48 mutants by pathogenic IBMPFD-VCPs
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- 作者：Takahiro Takata ; Yoko Kimura ; Yohei Ohnuma ; Junko Kawawaki ; Yukie Kakiyama ; Keiji Tanaka ; Akira Kakizuka
- 关键词：IBMPFD ; inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia ; ALS ; amyotrophic lateral sclerosis ; GFP ; green fluorescent protein
- 刊名：Journal of Structural Biology
- 出版年：2012
- 出版时间：August, 2012
- 年：2012
- 卷：179
- 期：2
- 页码：93-103
- 全文大小：1573 K
文摘
VCP/p97/Cdc48 is a hexameric ring-shaped AAA ATPase that participates in a wide variety of cellular functions. VCP is a very abundant protein in essentially all types of cells and is highly conserved among eukaryotes. To date, 19 different single amino acid-substitutions in VCP have been reported to cause IBMPFD (inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia), an autosomal dominant inherited human disease. Moreover, several similar single amino acid substitutions have been proposed to associate with a rare subclass of familial ALS. The mechanisms by which these mutations contribute to the pathogenesis are unclear. To elucidate potential functional differences between wild-type and pathogenic VCPs, we expressed both VCPs in yeast cdc48 mutants. We observed that all tested pathogenic VCPs suppressed the temperature-sensitive phenotype of cdc48 mutants more efficiently than wild-type VCP. In addition, pathogenic VCPs, but not wild-type VCP, were able to rescue a lethal cdc48 disruption. In yeast, pathogenic VCPs, but not wild-type VCP, formed apparent cytoplasmic foci, and these foci were transported to budding sites by the Myo2/actin-mediated transport machinery. The foci formation of pathogenic VCPs appeared to be associated with their suppression of the temperature-sensitive phenotype of cdc48 mutants. These results support the idea that the pathogenic VCP mutations create dominant gain-of-functions rather than a simple loss of functional VCP. Their unique properties in yeast could provide a convenient drug-screening system for the treatment of these diseases.