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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:The Journal of biological chemistry 2020-05, Vol.295 (21), p.7350-7361
Hauptverfasser: Miller, William P., Sunilkumar, Siddharth, Giordano, Joseph F., Toro, Allyson L., Barber, Alistair J., Dennis, Michael D.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 7361
container_issue 21
container_start_page 7350
container_title The Journal of biological chemistry
container_volume 295
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
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7247303</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0021925817502689</els_id><sourcerecordid>2390647282</sourcerecordid><originalsourceid>FETCH-LOGICAL-c447t-a123a209485a075d81a7f2dc1cd3f68935f37622f44e654d3967d891696da67f3</originalsourceid><addsrcrecordid>eNp1kc1PXCEUxYlpo1PbvSvDsps35es9Hi5MjNrW1NjE2KQ7wsB9ipmBJzAT3fVPL9PRiV3I4sIN5xxu-CF0QMmUEim-3M_s9PqEMjIllBPFd9CEkp43vKW_36EJIYw2irX9HvqQ8z2pSyi6i_Y4Y6rtBZ-gPzd3gHNJkDOuZYwhAx5TLOADvj4_O6PrblH7jJ03M6iHxge3tOBwfPTOFL_aJlRPqXkJig8Gz57wDzAjXethhFpCwVdpYNjBbTJrawwf0fvBzDN8et730a-v5zen35vLn98uTk8uGyuELI2hjBtGlOhbQ2TremrkwJyl1vGh6xVvBy47xgYhoGuF46qTrle0U50znRz4Pjre5I7L2QKcrbMkM9dj8guTnnQ0Xv9_E_ydvo0rLZmQnPAa8Pk5IMWHJeSiFz5bmM9NgLjMmnFFOiFZz6qUbKQ2xZwTDNtnKNFrcLqC0__A6Q24ajl8Pd7W8EKqCo42AqiftPKQdLYeQsXgE9iiXfRvp_8FEq6qAw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2390647282</pqid></control><display><type>article</type><title>The stress response protein REDD1 promotes diabetes-induced oxidative stress in the retina by Keap1-independent Nrf2 degradation</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Miller, William P. ; Sunilkumar, Siddharth ; Giordano, Joseph F. ; Toro, Allyson L. ; Barber, Alistair J. ; Dennis, Michael D.</creator><creatorcontrib>Miller, William P. ; Sunilkumar, Siddharth ; Giordano, Joseph F. ; Toro, Allyson L. ; Barber, Alistair J. ; Dennis, Michael D.</creatorcontrib><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><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>
fulltext fulltext
identifier ISSN: 0021-9258
ispartof The Journal of biological chemistry, 2020-05, Vol.295 (21), p.7350-7361
issn 0021-9258
1083-351X
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7247303
source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection
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
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-19T22%3A49%3A30IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20stress%20response%20protein%20REDD1%20promotes%20diabetes-induced%20oxidative%20stress%20in%20the%20retina%20by%20Keap1-independent%20Nrf2%20degradation&rft.jtitle=The%20Journal%20of%20biological%20chemistry&rft.au=Miller,%20William%20P.&rft.date=2020-05-22&rft.volume=295&rft.issue=21&rft.spage=7350&rft.epage=7361&rft.pages=7350-7361&rft.issn=0021-9258&rft.eissn=1083-351X&rft_id=info:doi/10.1074/jbc.RA120.013093&rft_dat=%3Cproquest_pubme%3E2390647282%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2390647282&rft_id=info:pmid/32295843&rft_els_id=S0021925817502689&rfr_iscdi=true