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.
Date: 2016
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
MeSH Terms:
  • Animals
  • Cataract/genetics*
  • Lens Capsule, Crystalline/metabolism*
  • Mice
  • Mutation*
  • Protein Aggregates*
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/biosynthesis*
  • Zebrafish Proteins/genetics
  • alpha-Crystallin A Chain/biosynthesis
  • alpha-Crystallin A Chain/genetics
  • gamma-Crystallins/biosynthesis*
  • gamma-Crystallins/genetics
PubMed: 27770023 Full text @ J. Biol. Chem.
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ABSTRACT
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 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.
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