Activation of the unfolded protein response by a cataract-associated αA-crystallin mutation.
αA-crystallin is a lens chaperone that plays an essential role in the transparency and refractive properties of the lens. Mutations in αA-crystallin have been associated with the development of hereditary cataracts. The R49C mutation of αA-crystallin (αA-R49C) was identified in a four-generation Caucasian family with hereditary cataracts. The αA-R49C protein forms larger-than-normal oligomers in the lens and has decreased solubility. This aberrant αA-R49C oligomerization suggests that protein folding is altered. However, whether activation of the unfolded protein response (UPR) occurs during crystallin mutation-induced cataract formation and whether the UPR causes cell death under these conditions is unclear. We investigated UPR activation in an in vivo mouse model of αA-R49C using immunoblot analysis of lens extracts. We found that expression of the endoplasmic reticulum (ER) chaperone, BiP, was 5-fold higher in homozygous αA-R49C lenses than in wild type lenses. Analysis of proteins typically expressed during the UPR revealed that ATF-4 and CHOP levels were also higher in homozygous lenses than in wild type lenses, while the opposite was true of ATF-6 and XBP-1. Taken together, these findings show that mutation of αA-crystallin induces activation of the UPR during cataract formation. They also suggest that the UPR is an important mediator of cell death observed in homozygous αA-R49C lenses.
Watson
Gregory W
GW
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Andley
Usha P
UP
D000818:Animals; D002386:Cataract / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D056811:Unfolded Protein Response; D038202:alpha-Crystallin A Chain / Q000235:genetics / Q000378:metabolism*
D038202:alpha-Crystallin A Chain