|ZFIN ID: ZDB-PUB-161025-16|
Expression of Cataract-linked γ-crystallin Variants in Zebrafish Reveals a Proteostasis Network that Senses Protein Stability
Wu, S.Y., Zou, P., Fuller, A.W., Mishra, S., Wang, Z., Schey, K.L., Mchaourab, H.S.
|Source:||The Journal of biological chemistry 291(49): 25387-25397 (Journal)|
|Registered Authors:||Wu, Shu-Yu (Simon)|
|Keywords:||aggregation, cataract, chaperone, crystallin, lens, proteostasis, small heat shock protein (sHsp), zebrafish|
|PubMed:||27770023 Full text @ J. Biol. Chem.|
Wu, S.Y., Zou, P., Fuller, A.W., Mishra, S., Wang, Z., Schey, K.L., Mchaourab, H.S. (2016) Expression of Cataract-linked γ-crystallin Variants in Zebrafish Reveals a Proteostasis Network that Senses Protein Stability. The Journal of biological chemistry. 291(49):25387-25397.
ABSTRACTThe 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 γB- and γD-crystallin mutants linked to dominant cataracts in mouse models. While thermodynamically destabilized and aggregation-prone, these mutants were found to have weak affinity to the resident chaperone α-crystallin in vitro To better understand the mechanism of the cataract phenotype, we transgenically expressed different γD-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 which 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 αA-crystallin had no significant effects on the penetrance of lens defects suggesting that its chaperone capacity is not limiting. While consistent with the prevailing hypothesis that a chaperone network is required for lens transparency, our results suggest that αA-crystallin may not be efficient to inhibit aggregation of lens γ-crystallin. Our work further implicates additional inputs/factors are involved in this underlying proteostasis network and demonstrates the utility of zebrafish as a platform to delineate mechanisms of cataract.