Human immunodeficiency virus-encoded Tat activates glycogen synthase kinase-3beta to antagonize nuclear factor-kappaB survival pathway in neurons
The pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated dementia is mediated by neuronal dysfunction and death, brought about by the action of soluble neurotoxic factors that are released by virally infected macrophages and microglia. Paradoxically, many candidate HIV-1 neurotoxin...
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Veröffentlicht in: | The European journal of neuroscience 2006-05, Vol.23 (10), p.2623 |
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creator | Sui, Ziye Sniderhan, Lynn F Fan, Shongshan Kazmierczak, Katarzyna Reisinger, Elizabeth Kovács, Attila D Potash, Mary Jane Dewhurst, Stephen Gelbard, Harris A Maggirwar, Sanjay B |
description | The pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated dementia is mediated by neuronal dysfunction and death, brought about by the action of soluble neurotoxic factors that are released by virally infected macrophages and microglia. Paradoxically, many candidate HIV-1 neurotoxins also possess the ability to activate nuclear factor-kappa B (NF-kappaB), which has a potent pro-survival effect in primary neurons. The present study explored this conundrum and investigated why NF-kappaB might fail to protect neurons that are exposed to candidate HIV-1 neurotoxins. Here, we evaluated the ability of virus-depleted conditioned medium produced by HIV-1-infected human macrophages (HIV-MCMs) to modulate NF-kappaB activity in neurons. We demonstrated that HIV-MCMs inhibit the normal signaling pathways that lead to NF-kappaB activation in neurons. This inhibitory effect of HIV-MCM is dependent upon the presence of HIV-1 Tat, which activates glycogen synthase kinase (GSK)-3beta in neurons. Activation of GSK-3beta, in turn, results in modification of the NF-kappaB subunit RelA at serine 468, thereby regulating the physical interaction of RelA with histone deacetylase-3 corepressor molecules. Furthermore, neutralization of Tat or inhibition of GSK-3beta activity prevents neuronal apoptosis induced by HIV-MCM. We conclude that HIV-1 Tat may compromise neuronal function and fate by interfering with normal survival pathways subserved by NF-kappaB. These findings may have important therapeutic implications for the management of HIV-1-associated dementia. |
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Paradoxically, many candidate HIV-1 neurotoxins also possess the ability to activate nuclear factor-kappa B (NF-kappaB), which has a potent pro-survival effect in primary neurons. The present study explored this conundrum and investigated why NF-kappaB might fail to protect neurons that are exposed to candidate HIV-1 neurotoxins. Here, we evaluated the ability of virus-depleted conditioned medium produced by HIV-1-infected human macrophages (HIV-MCMs) to modulate NF-kappaB activity in neurons. We demonstrated that HIV-MCMs inhibit the normal signaling pathways that lead to NF-kappaB activation in neurons. This inhibitory effect of HIV-MCM is dependent upon the presence of HIV-1 Tat, which activates glycogen synthase kinase (GSK)-3beta in neurons. Activation of GSK-3beta, in turn, results in modification of the NF-kappaB subunit RelA at serine 468, thereby regulating the physical interaction of RelA with histone deacetylase-3 corepressor molecules. Furthermore, neutralization of Tat or inhibition of GSK-3beta activity prevents neuronal apoptosis induced by HIV-MCM. We conclude that HIV-1 Tat may compromise neuronal function and fate by interfering with normal survival pathways subserved by NF-kappaB. These findings may have important therapeutic implications for the management of HIV-1-associated dementia.</description><identifier>ISSN: 0953-816X</identifier><identifier>PMID: 16817865</identifier><language>eng</language><publisher>France</publisher><subject>AIDS Dementia Complex - metabolism ; AIDS Dementia Complex - virology ; Animals ; Apoptosis - physiology ; Cells, Cultured ; Culture Media, Conditioned ; Enzyme Activation - physiology ; Gene Products, tat - metabolism ; Glycogen Synthase Kinase 3 - metabolism ; Glycogen Synthase Kinase 3 beta ; Histone Deacetylases - metabolism ; HIV-1 - metabolism ; Humans ; Immunoblotting ; Immunoprecipitation ; In Situ Nick-End Labeling ; Macrophages - metabolism ; Macrophages - virology ; Neurons - metabolism ; Neurons - pathology ; NF-kappa B - antagonists & inhibitors ; Rats ; Signal Transduction - physiology ; tat Gene Products, Human Immunodeficiency Virus ; Transcription Factor RelA - metabolism ; Transfection</subject><ispartof>The European journal of neuroscience, 2006-05, Vol.23 (10), p.2623</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16817865$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sui, Ziye</creatorcontrib><creatorcontrib>Sniderhan, Lynn F</creatorcontrib><creatorcontrib>Fan, Shongshan</creatorcontrib><creatorcontrib>Kazmierczak, Katarzyna</creatorcontrib><creatorcontrib>Reisinger, Elizabeth</creatorcontrib><creatorcontrib>Kovács, Attila D</creatorcontrib><creatorcontrib>Potash, Mary Jane</creatorcontrib><creatorcontrib>Dewhurst, Stephen</creatorcontrib><creatorcontrib>Gelbard, Harris A</creatorcontrib><creatorcontrib>Maggirwar, Sanjay B</creatorcontrib><title>Human immunodeficiency virus-encoded Tat activates glycogen synthase kinase-3beta to antagonize nuclear factor-kappaB survival pathway in neurons</title><title>The European journal of neuroscience</title><addtitle>Eur J Neurosci</addtitle><description>The pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated dementia is mediated by neuronal dysfunction and death, brought about by the action of soluble neurotoxic factors that are released by virally infected macrophages and microglia. Paradoxically, many candidate HIV-1 neurotoxins also possess the ability to activate nuclear factor-kappa B (NF-kappaB), which has a potent pro-survival effect in primary neurons. The present study explored this conundrum and investigated why NF-kappaB might fail to protect neurons that are exposed to candidate HIV-1 neurotoxins. Here, we evaluated the ability of virus-depleted conditioned medium produced by HIV-1-infected human macrophages (HIV-MCMs) to modulate NF-kappaB activity in neurons. We demonstrated that HIV-MCMs inhibit the normal signaling pathways that lead to NF-kappaB activation in neurons. This inhibitory effect of HIV-MCM is dependent upon the presence of HIV-1 Tat, which activates glycogen synthase kinase (GSK)-3beta in neurons. Activation of GSK-3beta, in turn, results in modification of the NF-kappaB subunit RelA at serine 468, thereby regulating the physical interaction of RelA with histone deacetylase-3 corepressor molecules. Furthermore, neutralization of Tat or inhibition of GSK-3beta activity prevents neuronal apoptosis induced by HIV-MCM. We conclude that HIV-1 Tat may compromise neuronal function and fate by interfering with normal survival pathways subserved by NF-kappaB. These findings may have important therapeutic implications for the management of HIV-1-associated dementia.</description><subject>AIDS Dementia Complex - metabolism</subject><subject>AIDS Dementia Complex - virology</subject><subject>Animals</subject><subject>Apoptosis - physiology</subject><subject>Cells, Cultured</subject><subject>Culture Media, Conditioned</subject><subject>Enzyme Activation - physiology</subject><subject>Gene Products, tat - metabolism</subject><subject>Glycogen Synthase Kinase 3 - metabolism</subject><subject>Glycogen Synthase Kinase 3 beta</subject><subject>Histone Deacetylases - metabolism</subject><subject>HIV-1 - metabolism</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Immunoprecipitation</subject><subject>In Situ Nick-End Labeling</subject><subject>Macrophages - metabolism</subject><subject>Macrophages - virology</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>NF-kappa B - antagonists & inhibitors</subject><subject>Rats</subject><subject>Signal Transduction - physiology</subject><subject>tat Gene Products, Human Immunodeficiency Virus</subject><subject>Transcription Factor RelA - metabolism</subject><subject>Transfection</subject><issn>0953-816X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kEFOwzAURLMA0VK4AvoXiJTEseMsoQKKhMSmC3bVr_3dmiZOZDtF4RbcGEvA6o1GmpFmLrJl0XKWy1K8L7LrED6KopCi5lfZohSybKTgy-x7M_XowPb95AZNxipLTs1wtn4KeZLJ1LDFCKiiPWOkAIduVsOBHITZxSMGgpN1CTnbU0SIA6CLeBic_SJwk-oIPZiUH3x-wnHEBwiTP6e2DkaMx0-cwTpwNPnBhZvs0mAX6PaPq2z79Lhdb_LXt-eX9f1rPvKa50wKUWPJRLE3whBpRU1R84o3qJOlTSllmt8WpUFWVaRaVSFnjRESWxSarbK739px2vekd6O3Pfp5938N-wES1mOy</recordid><startdate>200605</startdate><enddate>200605</enddate><creator>Sui, Ziye</creator><creator>Sniderhan, Lynn F</creator><creator>Fan, Shongshan</creator><creator>Kazmierczak, Katarzyna</creator><creator>Reisinger, Elizabeth</creator><creator>Kovács, Attila D</creator><creator>Potash, Mary Jane</creator><creator>Dewhurst, Stephen</creator><creator>Gelbard, Harris A</creator><creator>Maggirwar, Sanjay B</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>200605</creationdate><title>Human immunodeficiency virus-encoded Tat activates glycogen synthase kinase-3beta to antagonize nuclear factor-kappaB survival pathway in neurons</title><author>Sui, Ziye ; Sniderhan, Lynn F ; Fan, Shongshan ; Kazmierczak, Katarzyna ; Reisinger, Elizabeth ; Kovács, Attila D ; Potash, Mary Jane ; Dewhurst, Stephen ; Gelbard, Harris A ; Maggirwar, Sanjay B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p545-38664a1360bf6feedce7045257ad0bfdf188095901fa322ec9c2a537f68a9a6d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>AIDS Dementia Complex - metabolism</topic><topic>AIDS Dementia Complex - virology</topic><topic>Animals</topic><topic>Apoptosis - physiology</topic><topic>Cells, Cultured</topic><topic>Culture Media, Conditioned</topic><topic>Enzyme Activation - physiology</topic><topic>Gene Products, tat - metabolism</topic><topic>Glycogen Synthase Kinase 3 - metabolism</topic><topic>Glycogen Synthase Kinase 3 beta</topic><topic>Histone Deacetylases - metabolism</topic><topic>HIV-1 - metabolism</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Immunoprecipitation</topic><topic>In Situ Nick-End Labeling</topic><topic>Macrophages - metabolism</topic><topic>Macrophages - virology</topic><topic>Neurons - metabolism</topic><topic>Neurons - pathology</topic><topic>NF-kappa B - antagonists & inhibitors</topic><topic>Rats</topic><topic>Signal Transduction - physiology</topic><topic>tat Gene Products, Human Immunodeficiency Virus</topic><topic>Transcription Factor RelA - metabolism</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sui, Ziye</creatorcontrib><creatorcontrib>Sniderhan, Lynn F</creatorcontrib><creatorcontrib>Fan, Shongshan</creatorcontrib><creatorcontrib>Kazmierczak, Katarzyna</creatorcontrib><creatorcontrib>Reisinger, Elizabeth</creatorcontrib><creatorcontrib>Kovács, Attila D</creatorcontrib><creatorcontrib>Potash, Mary Jane</creatorcontrib><creatorcontrib>Dewhurst, Stephen</creatorcontrib><creatorcontrib>Gelbard, Harris A</creatorcontrib><creatorcontrib>Maggirwar, Sanjay B</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>The European journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sui, Ziye</au><au>Sniderhan, Lynn F</au><au>Fan, Shongshan</au><au>Kazmierczak, Katarzyna</au><au>Reisinger, Elizabeth</au><au>Kovács, Attila D</au><au>Potash, Mary Jane</au><au>Dewhurst, Stephen</au><au>Gelbard, Harris A</au><au>Maggirwar, Sanjay B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human immunodeficiency virus-encoded Tat activates glycogen synthase kinase-3beta to antagonize nuclear factor-kappaB survival pathway in neurons</atitle><jtitle>The European journal of neuroscience</jtitle><addtitle>Eur J Neurosci</addtitle><date>2006-05</date><risdate>2006</risdate><volume>23</volume><issue>10</issue><spage>2623</spage><pages>2623-</pages><issn>0953-816X</issn><abstract>The pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated dementia is mediated by neuronal dysfunction and death, brought about by the action of soluble neurotoxic factors that are released by virally infected macrophages and microglia. Paradoxically, many candidate HIV-1 neurotoxins also possess the ability to activate nuclear factor-kappa B (NF-kappaB), which has a potent pro-survival effect in primary neurons. The present study explored this conundrum and investigated why NF-kappaB might fail to protect neurons that are exposed to candidate HIV-1 neurotoxins. Here, we evaluated the ability of virus-depleted conditioned medium produced by HIV-1-infected human macrophages (HIV-MCMs) to modulate NF-kappaB activity in neurons. We demonstrated that HIV-MCMs inhibit the normal signaling pathways that lead to NF-kappaB activation in neurons. This inhibitory effect of HIV-MCM is dependent upon the presence of HIV-1 Tat, which activates glycogen synthase kinase (GSK)-3beta in neurons. Activation of GSK-3beta, in turn, results in modification of the NF-kappaB subunit RelA at serine 468, thereby regulating the physical interaction of RelA with histone deacetylase-3 corepressor molecules. Furthermore, neutralization of Tat or inhibition of GSK-3beta activity prevents neuronal apoptosis induced by HIV-MCM. We conclude that HIV-1 Tat may compromise neuronal function and fate by interfering with normal survival pathways subserved by NF-kappaB. These findings may have important therapeutic implications for the management of HIV-1-associated dementia.</abstract><cop>France</cop><pmid>16817865</pmid></addata></record> |
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subjects | AIDS Dementia Complex - metabolism AIDS Dementia Complex - virology Animals Apoptosis - physiology Cells, Cultured Culture Media, Conditioned Enzyme Activation - physiology Gene Products, tat - metabolism Glycogen Synthase Kinase 3 - metabolism Glycogen Synthase Kinase 3 beta Histone Deacetylases - metabolism HIV-1 - metabolism Humans Immunoblotting Immunoprecipitation In Situ Nick-End Labeling Macrophages - metabolism Macrophages - virology Neurons - metabolism Neurons - pathology NF-kappa B - antagonists & inhibitors Rats Signal Transduction - physiology tat Gene Products, Human Immunodeficiency Virus Transcription Factor RelA - metabolism Transfection |
title | Human immunodeficiency virus-encoded Tat activates glycogen synthase kinase-3beta to antagonize nuclear factor-kappaB survival pathway in neurons |
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