期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 291, 期 49, 页码 25387-25397出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.749606
关键词
aggregation; cataract; chaperone; crystallin; lens; proteostasis; small heat shock protein (sHsp); zebrafish
资金
- National Institutes of Health [R01 EY12018, R01 EY13462, P30 EY008126]
- Vanderbilt University Proteomics Facility in the Mass Spectrometry Research Center
- Vanderbilt University Medical Center Cell Imaging Shared Resource
The refractivity and transparency of the ocular lens is dependent on the stability and solubility of the crystallins in the fiber cells. A number of mutations of lens crystallins have been associated with dominant cataracts in humans and mice. Of particular interest were B- and D-crystallin mutants linked to dominant cataracts in mouse models. Although thermodynamically destabilized and aggregation-prone, these mutants were found to have weak affinity to the resident chaperone -crystallin in vitro. To better understand the mechanism of the cataract phenotype, we transgenically expressed different D-crystallin mutants in the zebrafish lens and observed a range of lens defects that arise primarily from the aggregation of the mutant proteins. Unlike mouse models, a strong correlation was observed between the severity and penetrance of the phenotype and the level of destabilization of the mutant. We interpret this result to reflect the presence of a proteostasis network that can sense protein stability. In the more destabilized mutants, the capacity of this network is overwhelmed, leading to the observed increase in phenotypic penetrance. Overexpression of A-crystallin had no significant effects on the penetrance of lens defects, suggesting that its chaperone capacity is not limiting. Although consistent with the prevailing hypothesis that a chaperone network is required for lens transparency, our results suggest that A-crystallin may not be efficient to inhibit aggregation of lens -crystallin. Furthermore, our work implicates additional inputs/factors in this underlying proteostasis network and demonstrates the utility of zebrafish as a platform to delineate mechanisms of cataract.
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