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Activation of Disulfide Redox Switch in REDD1 Promotes Oxidative Stress Under Hyperglycemic Conditions

The stress response protein regulated in development and DNA damage response 1 (REDD1) has been implicated in visual deficits in patients with diabetes. The aim here was to investigate the mechanism responsible for the increase in retinal REDD1 protein content that is observed with diabetes. We foun...

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Autores principales: Miller, William P., Sha, Congzhou M., Sunilkumar, Siddharth, Toro, Allyson L., VanCleave, Ashley M., Kimball, Scot R., Dokholyan, Nikolay V., Dennis, Michael D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9750946/
https://www.ncbi.nlm.nih.gov/pubmed/36170669
http://dx.doi.org/10.2337/db22-0355
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author Miller, William P.
Sha, Congzhou M.
Sunilkumar, Siddharth
Toro, Allyson L.
VanCleave, Ashley M.
Kimball, Scot R.
Dokholyan, Nikolay V.
Dennis, Michael D.
author_facet Miller, William P.
Sha, Congzhou M.
Sunilkumar, Siddharth
Toro, Allyson L.
VanCleave, Ashley M.
Kimball, Scot R.
Dokholyan, Nikolay V.
Dennis, Michael D.
author_sort Miller, William P.
collection PubMed
description The stress response protein regulated in development and DNA damage response 1 (REDD1) has been implicated in visual deficits in patients with diabetes. The aim here was to investigate the mechanism responsible for the increase in retinal REDD1 protein content that is observed with diabetes. We found that REDD1 protein expression was increased in the retina of streptozotocin-induced diabetic mice in the absence of a change in REDD1 mRNA abundance or ribosome association. Oral antioxidant supplementation reduced retinal oxidative stress and suppressed REDD1 protein expression in the retina of diabetic mice. In human retinal Müller cell cultures, hyperglycemic conditions increased oxidative stress, enhanced REDD1 expression, and inhibited REDD1 degradation independently of the proteasome. Hyperglycemic conditions promoted a redox-sensitive cross-strand disulfide bond in REDD1 at C150/C157 that was required for reduced REDD1 degradation. Discrete molecular dynamics simulations of REDD1 structure revealed allosteric regulation of a degron upon formation of the disulfide bond that disrupted lysosomal proteolysis of REDD1. REDD1 acetylation at K129 was required for REDD1 recognition by the cytosolic chaperone HSC70 and degradation by chaperone-mediated autophagy. Disruption of REDD1 allostery upon C150/C157 disulfide bond formation prevented the suppressive effect of hyperglycemic conditions on REDD1 degradation and reduced oxidative stress in cells exposed to hyperglycemic conditions. The results reveal redox regulation of REDD1 and demonstrate the role of a REDD1 disulfide switch in development of oxidative stress.
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spelling pubmed-97509462023-01-21 Activation of Disulfide Redox Switch in REDD1 Promotes Oxidative Stress Under Hyperglycemic Conditions Miller, William P. Sha, Congzhou M. Sunilkumar, Siddharth Toro, Allyson L. VanCleave, Ashley M. Kimball, Scot R. Dokholyan, Nikolay V. Dennis, Michael D. Diabetes Complications The stress response protein regulated in development and DNA damage response 1 (REDD1) has been implicated in visual deficits in patients with diabetes. The aim here was to investigate the mechanism responsible for the increase in retinal REDD1 protein content that is observed with diabetes. We found that REDD1 protein expression was increased in the retina of streptozotocin-induced diabetic mice in the absence of a change in REDD1 mRNA abundance or ribosome association. Oral antioxidant supplementation reduced retinal oxidative stress and suppressed REDD1 protein expression in the retina of diabetic mice. In human retinal Müller cell cultures, hyperglycemic conditions increased oxidative stress, enhanced REDD1 expression, and inhibited REDD1 degradation independently of the proteasome. Hyperglycemic conditions promoted a redox-sensitive cross-strand disulfide bond in REDD1 at C150/C157 that was required for reduced REDD1 degradation. Discrete molecular dynamics simulations of REDD1 structure revealed allosteric regulation of a degron upon formation of the disulfide bond that disrupted lysosomal proteolysis of REDD1. REDD1 acetylation at K129 was required for REDD1 recognition by the cytosolic chaperone HSC70 and degradation by chaperone-mediated autophagy. Disruption of REDD1 allostery upon C150/C157 disulfide bond formation prevented the suppressive effect of hyperglycemic conditions on REDD1 degradation and reduced oxidative stress in cells exposed to hyperglycemic conditions. The results reveal redox regulation of REDD1 and demonstrate the role of a REDD1 disulfide switch in development of oxidative stress. American Diabetes Association 2022-12 2022-09-28 /pmc/articles/PMC9750946/ /pubmed/36170669 http://dx.doi.org/10.2337/db22-0355 Text en © 2022 by the American Diabetes Association https://www.diabetesjournals.org/journals/pages/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/journals/pages/license.
spellingShingle Complications
Miller, William P.
Sha, Congzhou M.
Sunilkumar, Siddharth
Toro, Allyson L.
VanCleave, Ashley M.
Kimball, Scot R.
Dokholyan, Nikolay V.
Dennis, Michael D.
Activation of Disulfide Redox Switch in REDD1 Promotes Oxidative Stress Under Hyperglycemic Conditions
title Activation of Disulfide Redox Switch in REDD1 Promotes Oxidative Stress Under Hyperglycemic Conditions
title_full Activation of Disulfide Redox Switch in REDD1 Promotes Oxidative Stress Under Hyperglycemic Conditions
title_fullStr Activation of Disulfide Redox Switch in REDD1 Promotes Oxidative Stress Under Hyperglycemic Conditions
title_full_unstemmed Activation of Disulfide Redox Switch in REDD1 Promotes Oxidative Stress Under Hyperglycemic Conditions
title_short Activation of Disulfide Redox Switch in REDD1 Promotes Oxidative Stress Under Hyperglycemic Conditions
title_sort activation of disulfide redox switch in redd1 promotes oxidative stress under hyperglycemic conditions
topic Complications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9750946/
https://www.ncbi.nlm.nih.gov/pubmed/36170669
http://dx.doi.org/10.2337/db22-0355
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