O -GlcNAcylation alters the selection of mRNAs for translation and promotes 4E-BP1-dependent mitochondrial dysfunction in the retina.

Autor:	Dierschke SK; From the Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania 17033., Miller WP; From the Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania 17033., Favate JS; the Department of Genetics, Rutgers University, Piscataway, New Jersey 08854., Shah P; the Department of Genetics, Rutgers University, Piscataway, New Jersey 08854., Imamura Kawasawa Y; the Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania 17033, and., Salzberg AC; the Department of Biochemistry and Molecular Biology, Institute for Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania 17033., Kimball SR; From the Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania 17033., Jefferson LS; From the Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania 17033., Dennis MD; From the Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania 17033, mdennis@psu.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2019 Apr 05; Vol. 294 (14), pp. 5508-5520. Date of Electronic Publication: 2019 Feb 07.
DOI:	10.1074/jbc.RA119.007494
Abstrakt:	Diabetes promotes the posttranslational modification of proteins by O- linked addition of GlcNAc ( O- GlcNAcylation) to Ser/Thr residues of proteins and thereby contributes to diabetic complications. In the retina of diabetic mice, the repressor of mRNA translation, eIF4E-binding protein 1 (4E-BP1), is O- GlcNAcylated, and sequestration of the cap-binding protein eukaryotic translation initiation factor (eIF4E) is enhanced. O- GlcNAcylation has also been detected on several eukaryotic translation initiation factors and ribosomal proteins. However, the functional consequence of this modification is unknown. Here, using ribosome profiling, we evaluated the effect of enhanced O- GlcNAcylation on retinal gene expression. Mice receiving thiamet G (TMG), an inhibitor of the O- GlcNAc hydrolase O- GlcNAcase, exhibited enhanced retinal protein O- GlcNAcylation. The principal effect of TMG on retinal gene expression was observed in ribosome-associated mRNAs ( i.e. mRNAs undergoing translation), as less than 1% of mRNAs exhibited changes in abundance. Remarkably, ∼19% of the transcriptome exhibited TMG-induced changes in ribosome occupancy, with 1912 mRNAs having reduced and 1683 mRNAs having increased translational rates. In the retina, the effect of O- GlcNAcase inhibition on translation of specific mitochondrial proteins, including superoxide dismutase 2 (SOD2), depended on 4E-BP1/2. O- GlcNAcylation enhanced cellular respiration and promoted mitochondrial superoxide levels in WT cells, and 4E-BP1/2 deletion prevented O- GlcNAcylation-induced mitochondrial superoxide in cells in culture and in the retina. The retina of diabetic WT mice exhibited increased reactive oxygen species levels, an effect not observed in diabetic 4E-BP1/2-deficient mice. These findings provide evidence for a mechanism whereby diabetes-induced O- GlcNAcylation promotes oxidative stress in the retina by altering the selection of mRNAs for translation. (© 2019 Dierschke et al.)
Databáze:	MEDLINE
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