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Invest Ophthalmol Vis Sci. 2016 Mar;57(3):1327-37. doi: 10.1167/iovs.15-18719.

The Translational Repressor 4E-BP1 Contributes to Diabetes-Induced Visual Dysfunction.

Author information

1
Department of Cellular and Molecular Physiology The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States.
2
Department of Cellular and Molecular Physiology The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States 2Department of Ophthalmology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United.

Abstract

PURPOSE:

The translational repressor 4E-BP1 interacts with the mRNA cap-binding protein eIF4E and thereby promotes cap-independent translation of mRNAs encoding proteins that contribute to diabetic retinopathy. Interaction of 4E-BP1 with eIF4E is enhanced in the retina of diabetic rodents, at least in part, as a result of elevated 4E-BP1 protein expression. In the present study, we examined the role of 4E-BP1 in diabetes-induced visual dysfunction, as well as the mechanism whereby hyperglycemia promotes 4E-BP1 expression.

METHODS:

Nondiabetic and diabetic wild-type and 4E-BP1/2 knockout mice were evaluated for visual function using a virtual optomotor test (Optomotry). Retinas were harvested from nondiabetic and type 1 diabetic mice and analyzed for protein abundance and posttranslational modifications. Similar analyses were performed on cells in culture exposed to hyperglycemic conditions or an O-GlcNAcase inhibitor (Thiamet G [TMG]).

RESULTS:

Diabetes-induced visual dysfunction was delayed in mice deficient of 4E-BP1/2 as compared to controls. 4E-BP1 protein expression was enhanced by hyperglycemia in the retina of diabetic rodents and by hyperglycemic conditions in retinal cells in culture. A similar elevation in 4E-BP1 expression was observed with TMG. The rate of 4E-BP1 degradation was significantly prolonged by either hyperglycemic conditions or TMG. A PEST motif in the C-terminus of 4E-BP1 regulated polyubiquitination, turnover, and binding of an E3 ubiquitin ligase complex containing CUL3.

CONCLUSIONS:

The findings support a model whereby elevated 4E-BP1 expression observed in the retina of diabetic rodents is the result of O-GlcNAcylation of 4E-BP1 within its PEST motif.

PMID:
26998719
PMCID:
PMC4811182
DOI:
10.1167/iovs.15-18719
[Indexed for MEDLINE]
Free PMC Article

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