The stress response protein REDD1 promotes diabetes-induced oxidative stress in the retina by Keap1-independent Nrf2 degradation
The transcription factor nuclear factor erythroid-2–related factor 2 (Nrf2) plays a critical role in reducing oxidative stress by promoting the expression of antioxidant genes. Both individuals with diabetes and preclinical diabetes models exhibit evidence of a defect in retinal Nrf2 activation. We...
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Veröffentlicht in: | The Journal of biological chemistry 2020-05, Vol.295 (21), p.7350-7361 |
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creator | Miller, William P. Sunilkumar, Siddharth Giordano, Joseph F. Toro, Allyson L. Barber, Alistair J. Dennis, Michael D. |
description | The transcription factor nuclear factor erythroid-2–related factor 2 (Nrf2) plays a critical role in reducing oxidative stress by promoting the expression of antioxidant genes. Both individuals with diabetes and preclinical diabetes models exhibit evidence of a defect in retinal Nrf2 activation. We recently demonstrated that increased expression of the stress response protein regulated in development and DNA damage 1 (REDD1) is necessary for the development of oxidative stress in the retina of streptozotocin-induced diabetic mice. In the present study, we tested the hypothesis that REDD1 suppresses the retinal antioxidant response to diabetes by repressing Nrf2 function. We found that REDD1 ablation enhances Nrf2 DNA-binding activity in the retina and that the suppressive effect of diabetes on Nrf2 activity is absent in the retina of REDD1-deficient mice compared with WT. In human MIO-M1 Müller cell cultures, REDD1 deletion prevented oxidative stress in response to hyperglycemic conditions, and this protective effect required Nrf2. REDD1 suppressed Nrf2 stability by promoting its proteasomal degradation independently of Nrf2's interaction with Kelch-like ECH-associated protein 1 (Keap1), but REDD1-mediated Nrf2 degradation required glycogen synthase kinase 3 (GSK3) activity and Ser-351/Ser-356 of Nrf2. Diabetes diminished inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser-9 in the retina of WT mice but not in REDD1-deficient mice. Pharmacological inhibition of GSK3 enhanced Nrf2 activity and prevented oxidative stress in the retina of diabetic mice. The findings support a model wherein hyperglycemia-induced REDD1 blunts the Nrf2 antioxidant response to diabetes by activating GSK3, which, in turn, phosphorylates Nrf2 to promote its degradation. |
doi_str_mv | 10.1074/jbc.RA120.013093 |
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Both individuals with diabetes and preclinical diabetes models exhibit evidence of a defect in retinal Nrf2 activation. We recently demonstrated that increased expression of the stress response protein regulated in development and DNA damage 1 (REDD1) is necessary for the development of oxidative stress in the retina of streptozotocin-induced diabetic mice. In the present study, we tested the hypothesis that REDD1 suppresses the retinal antioxidant response to diabetes by repressing Nrf2 function. We found that REDD1 ablation enhances Nrf2 DNA-binding activity in the retina and that the suppressive effect of diabetes on Nrf2 activity is absent in the retina of REDD1-deficient mice compared with WT. In human MIO-M1 Müller cell cultures, REDD1 deletion prevented oxidative stress in response to hyperglycemic conditions, and this protective effect required Nrf2. REDD1 suppressed Nrf2 stability by promoting its proteasomal degradation independently of Nrf2's interaction with Kelch-like ECH-associated protein 1 (Keap1), but REDD1-mediated Nrf2 degradation required glycogen synthase kinase 3 (GSK3) activity and Ser-351/Ser-356 of Nrf2. Diabetes diminished inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser-9 in the retina of WT mice but not in REDD1-deficient mice. Pharmacological inhibition of GSK3 enhanced Nrf2 activity and prevented oxidative stress in the retina of diabetic mice. The findings support a model wherein hyperglycemia-induced REDD1 blunts the Nrf2 antioxidant response to diabetes by activating GSK3, which, in turn, phosphorylates Nrf2 to promote its degradation.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.RA120.013093</identifier><identifier>PMID: 32295843</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Cell Line ; diabetes ; Diabetes Mellitus, Experimental - genetics ; Diabetes Mellitus, Experimental - metabolism ; Diabetes Mellitus, Experimental - pathology ; glycogen synthase kinase 3 (GSK-3) ; Humans ; hyperglycemia ; Kelch-Like ECH-Associated Protein 1 - genetics ; Kelch-Like ECH-Associated Protein 1 - metabolism ; Mice ; Mice, Knockout ; Molecular Bases of Disease ; NF-E2-Related Factor 2 - genetics ; NF-E2-Related Factor 2 - metabolism ; nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2) ; Oxidative Stress ; post-translational modification (PTM) ; Proteolysis ; reactive oxygen species (ROS) ; retina ; Retina - metabolism ; Retina - pathology ; retinopathy ; Transcription Factors - genetics ; Transcription Factors - metabolism</subject><ispartof>The Journal of biological chemistry, 2020-05, Vol.295 (21), p.7350-7361</ispartof><rights>2020 © 2020 Miller et al.</rights><rights>2020 Miller et al.</rights><rights>2020 Miller et al. 2020 Miller et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-a123a209485a075d81a7f2dc1cd3f68935f37622f44e654d3967d891696da67f3</citedby><cites>FETCH-LOGICAL-c447t-a123a209485a075d81a7f2dc1cd3f68935f37622f44e654d3967d891696da67f3</cites><orcidid>0000-0003-0157-6389 ; 0000-0003-3271-932X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247303/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247303/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32295843$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Miller, William P.</creatorcontrib><creatorcontrib>Sunilkumar, Siddharth</creatorcontrib><creatorcontrib>Giordano, Joseph F.</creatorcontrib><creatorcontrib>Toro, Allyson L.</creatorcontrib><creatorcontrib>Barber, Alistair J.</creatorcontrib><creatorcontrib>Dennis, Michael D.</creatorcontrib><title>The stress response protein REDD1 promotes diabetes-induced oxidative stress in the retina by Keap1-independent Nrf2 degradation</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The transcription factor nuclear factor erythroid-2–related factor 2 (Nrf2) plays a critical role in reducing oxidative stress by promoting the expression of antioxidant genes. Both individuals with diabetes and preclinical diabetes models exhibit evidence of a defect in retinal Nrf2 activation. We recently demonstrated that increased expression of the stress response protein regulated in development and DNA damage 1 (REDD1) is necessary for the development of oxidative stress in the retina of streptozotocin-induced diabetic mice. In the present study, we tested the hypothesis that REDD1 suppresses the retinal antioxidant response to diabetes by repressing Nrf2 function. We found that REDD1 ablation enhances Nrf2 DNA-binding activity in the retina and that the suppressive effect of diabetes on Nrf2 activity is absent in the retina of REDD1-deficient mice compared with WT. In human MIO-M1 Müller cell cultures, REDD1 deletion prevented oxidative stress in response to hyperglycemic conditions, and this protective effect required Nrf2. REDD1 suppressed Nrf2 stability by promoting its proteasomal degradation independently of Nrf2's interaction with Kelch-like ECH-associated protein 1 (Keap1), but REDD1-mediated Nrf2 degradation required glycogen synthase kinase 3 (GSK3) activity and Ser-351/Ser-356 of Nrf2. Diabetes diminished inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser-9 in the retina of WT mice but not in REDD1-deficient mice. Pharmacological inhibition of GSK3 enhanced Nrf2 activity and prevented oxidative stress in the retina of diabetic mice. The findings support a model wherein hyperglycemia-induced REDD1 blunts the Nrf2 antioxidant response to diabetes by activating GSK3, which, in turn, phosphorylates Nrf2 to promote its degradation.</description><subject>Animals</subject><subject>Cell Line</subject><subject>diabetes</subject><subject>Diabetes Mellitus, Experimental - genetics</subject><subject>Diabetes Mellitus, Experimental - metabolism</subject><subject>Diabetes Mellitus, Experimental - pathology</subject><subject>glycogen synthase kinase 3 (GSK-3)</subject><subject>Humans</subject><subject>hyperglycemia</subject><subject>Kelch-Like ECH-Associated Protein 1 - genetics</subject><subject>Kelch-Like ECH-Associated Protein 1 - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Molecular Bases of Disease</subject><subject>NF-E2-Related Factor 2 - genetics</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2)</subject><subject>Oxidative Stress</subject><subject>post-translational modification (PTM)</subject><subject>Proteolysis</subject><subject>reactive oxygen species (ROS)</subject><subject>retina</subject><subject>Retina - metabolism</subject><subject>Retina - pathology</subject><subject>retinopathy</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1PXCEUxYlpo1PbvSvDsps35es9Hi5MjNrW1NjE2KQ7wsB9ipmBJzAT3fVPL9PRiV3I4sIN5xxu-CF0QMmUEim-3M_s9PqEMjIllBPFd9CEkp43vKW_36EJIYw2irX9HvqQ8z2pSyi6i_Y4Y6rtBZ-gPzd3gHNJkDOuZYwhAx5TLOADvj4_O6PrblH7jJ03M6iHxge3tOBwfPTOFL_aJlRPqXkJig8Gz57wDzAjXethhFpCwVdpYNjBbTJrawwf0fvBzDN8et730a-v5zen35vLn98uTk8uGyuELI2hjBtGlOhbQ2TremrkwJyl1vGh6xVvBy47xgYhoGuF46qTrle0U50znRz4Pjre5I7L2QKcrbMkM9dj8guTnnQ0Xv9_E_ydvo0rLZmQnPAa8Pk5IMWHJeSiFz5bmM9NgLjMmnFFOiFZz6qUbKQ2xZwTDNtnKNFrcLqC0__A6Q24ajl8Pd7W8EKqCo42AqiftPKQdLYeQsXgE9iiXfRvp_8FEq6qAw</recordid><startdate>20200522</startdate><enddate>20200522</enddate><creator>Miller, William P.</creator><creator>Sunilkumar, Siddharth</creator><creator>Giordano, Joseph F.</creator><creator>Toro, Allyson L.</creator><creator>Barber, Alistair J.</creator><creator>Dennis, Michael D.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0157-6389</orcidid><orcidid>https://orcid.org/0000-0003-3271-932X</orcidid></search><sort><creationdate>20200522</creationdate><title>The stress response protein REDD1 promotes diabetes-induced oxidative stress in the retina by Keap1-independent Nrf2 degradation</title><author>Miller, William P. ; Sunilkumar, Siddharth ; Giordano, Joseph F. ; Toro, Allyson L. ; Barber, Alistair J. ; Dennis, Michael D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-a123a209485a075d81a7f2dc1cd3f68935f37622f44e654d3967d891696da67f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Cell Line</topic><topic>diabetes</topic><topic>Diabetes Mellitus, Experimental - genetics</topic><topic>Diabetes Mellitus, Experimental - metabolism</topic><topic>Diabetes Mellitus, Experimental - pathology</topic><topic>glycogen synthase kinase 3 (GSK-3)</topic><topic>Humans</topic><topic>hyperglycemia</topic><topic>Kelch-Like ECH-Associated Protein 1 - genetics</topic><topic>Kelch-Like ECH-Associated Protein 1 - metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Molecular Bases of Disease</topic><topic>NF-E2-Related Factor 2 - genetics</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2)</topic><topic>Oxidative Stress</topic><topic>post-translational modification (PTM)</topic><topic>Proteolysis</topic><topic>reactive oxygen species (ROS)</topic><topic>retina</topic><topic>Retina - metabolism</topic><topic>Retina - pathology</topic><topic>retinopathy</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Miller, William P.</creatorcontrib><creatorcontrib>Sunilkumar, Siddharth</creatorcontrib><creatorcontrib>Giordano, Joseph F.</creatorcontrib><creatorcontrib>Toro, Allyson L.</creatorcontrib><creatorcontrib>Barber, Alistair J.</creatorcontrib><creatorcontrib>Dennis, Michael D.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Miller, William P.</au><au>Sunilkumar, Siddharth</au><au>Giordano, Joseph F.</au><au>Toro, Allyson L.</au><au>Barber, Alistair J.</au><au>Dennis, Michael D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The stress response protein REDD1 promotes diabetes-induced oxidative stress in the retina by Keap1-independent Nrf2 degradation</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2020-05-22</date><risdate>2020</risdate><volume>295</volume><issue>21</issue><spage>7350</spage><epage>7361</epage><pages>7350-7361</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The transcription factor nuclear factor erythroid-2–related factor 2 (Nrf2) plays a critical role in reducing oxidative stress by promoting the expression of antioxidant genes. Both individuals with diabetes and preclinical diabetes models exhibit evidence of a defect in retinal Nrf2 activation. We recently demonstrated that increased expression of the stress response protein regulated in development and DNA damage 1 (REDD1) is necessary for the development of oxidative stress in the retina of streptozotocin-induced diabetic mice. In the present study, we tested the hypothesis that REDD1 suppresses the retinal antioxidant response to diabetes by repressing Nrf2 function. We found that REDD1 ablation enhances Nrf2 DNA-binding activity in the retina and that the suppressive effect of diabetes on Nrf2 activity is absent in the retina of REDD1-deficient mice compared with WT. In human MIO-M1 Müller cell cultures, REDD1 deletion prevented oxidative stress in response to hyperglycemic conditions, and this protective effect required Nrf2. REDD1 suppressed Nrf2 stability by promoting its proteasomal degradation independently of Nrf2's interaction with Kelch-like ECH-associated protein 1 (Keap1), but REDD1-mediated Nrf2 degradation required glycogen synthase kinase 3 (GSK3) activity and Ser-351/Ser-356 of Nrf2. Diabetes diminished inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser-9 in the retina of WT mice but not in REDD1-deficient mice. Pharmacological inhibition of GSK3 enhanced Nrf2 activity and prevented oxidative stress in the retina of diabetic mice. The findings support a model wherein hyperglycemia-induced REDD1 blunts the Nrf2 antioxidant response to diabetes by activating GSK3, which, in turn, phosphorylates Nrf2 to promote its degradation.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32295843</pmid><doi>10.1074/jbc.RA120.013093</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-0157-6389</orcidid><orcidid>https://orcid.org/0000-0003-3271-932X</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Cell Line diabetes Diabetes Mellitus, Experimental - genetics Diabetes Mellitus, Experimental - metabolism Diabetes Mellitus, Experimental - pathology glycogen synthase kinase 3 (GSK-3) Humans hyperglycemia Kelch-Like ECH-Associated Protein 1 - genetics Kelch-Like ECH-Associated Protein 1 - metabolism Mice Mice, Knockout Molecular Bases of Disease NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - metabolism nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2) Oxidative Stress post-translational modification (PTM) Proteolysis reactive oxygen species (ROS) retina Retina - metabolism Retina - pathology retinopathy Transcription Factors - genetics Transcription Factors - metabolism |
title | The stress response protein REDD1 promotes diabetes-induced oxidative stress in the retina by Keap1-independent Nrf2 degradation |
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