Diabetes enhances translation of Cd40 mRNA in murine retinal Müller glia via a 4E-BP1/2--dependent mechanism.
In: Journal of Biological Chemistry, Jg. 295 (2020-07-31), Heft 31, S. 10831-10845
Online
academicJournal
Zugriff:
Activation of the immune costimulatory molecule cluster of differentiation 40 (CD40) in Müller glia has been implicated in the initiation of diabetes-induced retinal inflammation. Results from previous studies support that CD40 protein expression is elevated in Müller glia of diabetic mice; however, the mechanisms responsible for this increase have not been explored. Here, we evaluated the hypothesis that diabetes augments translation of the Cd40 mRNA. Mice receiving thiamet G (TMG), an inhibitor of the O-GlcNAc hydrolase O-GlcNAcase, exhibited enhanced retinal protein O-GlcNAcylation and increased Cd40 mRNA translation. TMG administration also promoted Cd40 mRNA association with Müller cell--specific ribosomes isolated from the retina of RiboTag mice. Similar effects on O-GlcNAcylation and Cd40 mRNA translation were also observed in the retina of a mouse model of type 1 diabetes. In cultured cells, TMG promoted sequestration of the cap-binding protein eIF4E (eukaryotic translation in initiation factor 4E) by 4E-BP1 (eIF4E-binding protein 1) and enhanced cap-independent Cd40 mRNA translation as assessed by a bicistronic reporter that contained the 59-UTR of the Cd40 mRNA. Ablation of 4E-BP1/2 prevented the increase in Cd40 mRNA translation in TMGexposed cells, and expression of a 4E-BP1 variant that constitutively sequesters eIF4E promoted reporter activity. Extending on the cell culture results, we found that in contrast to WT mice, diabetic 4E-BP1/2--deficient mice did not exhibit enhanced retinal Cd40 mRNA translation and failed to up-regulate expression of the inflammatory marker nitric-oxide synthase 2. These findings support a model wherein diabetes-induced O-GlcNAcylation of 4E-BP1 promotes Cd40 mRNA translation in Müller glia. [ABSTRACT FROM AUTHOR]
Titel: |
Diabetes enhances translation of Cd40 mRNA in murine retinal Müller glia via a 4E-BP1/2--dependent mechanism.
|
---|---|
Autor/in / Beteiligte Person: | Dierschke, Sadie K. ; Toro, Allyson L. ; Miller, William P. ; Sunilkumar, Siddharth ; Dennis, Michael D. |
Link: | |
Zeitschrift: | Journal of Biological Chemistry, Jg. 295 (2020-07-31), Heft 31, S. 10831-10845 |
Veröffentlichung: | 2020 |
Medientyp: | academicJournal |
ISSN: | 0021-9258 (print) |
DOI: | 10.1074/jbc.RA120.013711 |
Schlagwort: |
|
Sonstiges: |
|