The HIV-1 Nef Protein and Phagocyte NADPH Oxidase Activation
Nef, a multifunctional HIV protein, activates the Vav/Rac/p21-activated kinase (PAK) signaling pathway. Given the potential role of this pathway in the activation of the phagocyte NADPH oxidase, we have investigated the effect of the HIV-1 Nef protein on the phagocyte respiratory burst. Microglia (c...
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| Veröffentlicht in: | The Journal of biological chemistry 2002-11, Vol.277 (44), p.42136-42143 |
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| container_title | The Journal of biological chemistry |
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| creator | Vilhardt, Frederik Plastre, Olivier Sawada, Makoto Suzuki, Kazuo Wiznerowicz, Maciej Kiyokawa, Etsuko Trono, Didier Krause, Karl-Heinz |
| description | Nef, a multifunctional HIV protein, activates the Vav/Rac/p21-activated kinase (PAK) signaling pathway. Given the potential
role of this pathway in the activation of the phagocyte NADPH oxidase, we have investigated the effect of the HIV-1 Nef protein
on the phagocyte respiratory burst. Microglia (cell line and primary culture) were transduced with lentiviral expression vectors.
Expression of Nef did not activate the NADPH oxidase by itself but led to a massive enhancement of the responses to a variety
of stimuli (Ca 2+ ionophore, formyl peptide, endotoxin). These effects were not caused by up-regulation of phagocyte NADPH oxidase subunits.
Nef mutants lacking motifs involved in the interaction with Vav and PAK failed to reproduce the effects of wild type Nef,
suggesting a role for the Vav/Rac/PAK signaling pathway. The following results suggest a key role for Rac in the priming effect
of Nef. (i) Inactivation of Rac by Clostridium difficile toxin B abolished the Nef effect. (ii) The fraction of activated Rac1 was increased in Nef-transduced cells, and (iii) the
dominant positive Rac1(V12) mutant mimicked the effect of Nef. These results are to our knowledge the first analysis of the
effect of Rac activation on the NADPH oxidase in intact phagocytes. Rac activation is not sufficient to stimulate the phagocyte
NADPH oxidase; however, it markedly enhances the NADPH oxidase response to other stimuli. |
| doi_str_mv | 10.1074/jbc.M200862200 |
| format | Article |
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role of this pathway in the activation of the phagocyte NADPH oxidase, we have investigated the effect of the HIV-1 Nef protein
on the phagocyte respiratory burst. Microglia (cell line and primary culture) were transduced with lentiviral expression vectors.
Expression of Nef did not activate the NADPH oxidase by itself but led to a massive enhancement of the responses to a variety
of stimuli (Ca 2+ ionophore, formyl peptide, endotoxin). These effects were not caused by up-regulation of phagocyte NADPH oxidase subunits.
Nef mutants lacking motifs involved in the interaction with Vav and PAK failed to reproduce the effects of wild type Nef,
suggesting a role for the Vav/Rac/PAK signaling pathway. The following results suggest a key role for Rac in the priming effect
of Nef. (i) Inactivation of Rac by Clostridium difficile toxin B abolished the Nef effect. (ii) The fraction of activated Rac1 was increased in Nef-transduced cells, and (iii) the
dominant positive Rac1(V12) mutant mimicked the effect of Nef. These results are to our knowledge the first analysis of the
effect of Rac activation on the NADPH oxidase in intact phagocytes. Rac activation is not sufficient to stimulate the phagocyte
NADPH oxidase; however, it markedly enhances the NADPH oxidase response to other stimuli.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M200862200</identifier><identifier>PMID: 12207012</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Amino Acid Motifs ; Animals ; Cell Line ; Enzyme Activation ; Gene Products, nef - physiology ; HIV-1 - physiology ; Mice ; Microglia - enzymology ; NADPH Oxidases - metabolism ; nef Gene Products, Human Immunodeficiency Virus ; Oncogene Proteins - physiology ; Phagocytes - enzymology ; Protein Subunits ; Proto-Oncogene Proteins c-vav ; rac1 GTP-Binding Protein - physiology ; src Homology Domains ; Superoxides - metabolism</subject><ispartof>The Journal of biological chemistry, 2002-11, Vol.277 (44), p.42136-42143</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c457t-d0ef42399b05c2262aa702cc3fbe6da194dcbdcdabf3cb440dc89b55704b667e3</citedby><cites>FETCH-LOGICAL-c457t-d0ef42399b05c2262aa702cc3fbe6da194dcbdcdabf3cb440dc89b55704b667e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12207012$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vilhardt, Frederik</creatorcontrib><creatorcontrib>Plastre, Olivier</creatorcontrib><creatorcontrib>Sawada, Makoto</creatorcontrib><creatorcontrib>Suzuki, Kazuo</creatorcontrib><creatorcontrib>Wiznerowicz, Maciej</creatorcontrib><creatorcontrib>Kiyokawa, Etsuko</creatorcontrib><creatorcontrib>Trono, Didier</creatorcontrib><creatorcontrib>Krause, Karl-Heinz</creatorcontrib><title>The HIV-1 Nef Protein and Phagocyte NADPH Oxidase Activation</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Nef, a multifunctional HIV protein, activates the Vav/Rac/p21-activated kinase (PAK) signaling pathway. Given the potential
role of this pathway in the activation of the phagocyte NADPH oxidase, we have investigated the effect of the HIV-1 Nef protein
on the phagocyte respiratory burst. Microglia (cell line and primary culture) were transduced with lentiviral expression vectors.
Expression of Nef did not activate the NADPH oxidase by itself but led to a massive enhancement of the responses to a variety
of stimuli (Ca 2+ ionophore, formyl peptide, endotoxin). These effects were not caused by up-regulation of phagocyte NADPH oxidase subunits.
Nef mutants lacking motifs involved in the interaction with Vav and PAK failed to reproduce the effects of wild type Nef,
suggesting a role for the Vav/Rac/PAK signaling pathway. The following results suggest a key role for Rac in the priming effect
of Nef. (i) Inactivation of Rac by Clostridium difficile toxin B abolished the Nef effect. (ii) The fraction of activated Rac1 was increased in Nef-transduced cells, and (iii) the
dominant positive Rac1(V12) mutant mimicked the effect of Nef. These results are to our knowledge the first analysis of the
effect of Rac activation on the NADPH oxidase in intact phagocytes. Rac activation is not sufficient to stimulate the phagocyte
NADPH oxidase; however, it markedly enhances the NADPH oxidase response to other stimuli.</description><subject>Amino Acid Motifs</subject><subject>Animals</subject><subject>Cell Line</subject><subject>Enzyme Activation</subject><subject>Gene Products, nef - physiology</subject><subject>HIV-1 - physiology</subject><subject>Mice</subject><subject>Microglia - enzymology</subject><subject>NADPH Oxidases - metabolism</subject><subject>nef Gene Products, Human Immunodeficiency Virus</subject><subject>Oncogene Proteins - physiology</subject><subject>Phagocytes - enzymology</subject><subject>Protein Subunits</subject><subject>Proto-Oncogene Proteins c-vav</subject><subject>rac1 GTP-Binding Protein - physiology</subject><subject>src Homology Domains</subject><subject>Superoxides - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEtPwkAUhSdGI4huXZpZGHfFebXTJm4IPiBBYIHG3WQet3QIpdgpKv_eGkg8i3s23z2LD6FrSvqUSHG_Mrb_yghJE9beE9SlJOURj-nHKeoSwmiUsTjtoIsQVqSNyOg56tAWloSyLnpYFIBH4_eI4inkeF5XDfgN1huH54VeVnbfAJ4OHucjPPvxTgfAA9v4L934anOJznK9DnB17B56e35aDEfRZPYyHg4mkRWxbCJHIBeMZ5khsWUsYVpLwqzluYHEaZoJZ42zTpucWyMEcTbNTBxLIkySSOA9dHfY3dbV5w5Co0ofLKzXegPVLiiaxiSVSdaC_QNo6yqEGnK1rX2p672iRP35Uq0v9e-rfbg5Lu9MCe4fPwpqgdsDUPhl8e1rUMZXtoBSMSmVEEowyhP-C97HcDo</recordid><startdate>20021101</startdate><enddate>20021101</enddate><creator>Vilhardt, Frederik</creator><creator>Plastre, Olivier</creator><creator>Sawada, Makoto</creator><creator>Suzuki, Kazuo</creator><creator>Wiznerowicz, Maciej</creator><creator>Kiyokawa, Etsuko</creator><creator>Trono, Didier</creator><creator>Krause, Karl-Heinz</creator><general>American Society for Biochemistry and Molecular Biology</general><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>7U9</scope><scope>H94</scope></search><sort><creationdate>20021101</creationdate><title>The HIV-1 Nef Protein and Phagocyte NADPH Oxidase Activation</title><author>Vilhardt, Frederik ; Plastre, Olivier ; Sawada, Makoto ; Suzuki, Kazuo ; Wiznerowicz, Maciej ; Kiyokawa, Etsuko ; Trono, Didier ; Krause, Karl-Heinz</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c457t-d0ef42399b05c2262aa702cc3fbe6da194dcbdcdabf3cb440dc89b55704b667e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Amino Acid Motifs</topic><topic>Animals</topic><topic>Cell Line</topic><topic>Enzyme Activation</topic><topic>Gene Products, nef - physiology</topic><topic>HIV-1 - physiology</topic><topic>Mice</topic><topic>Microglia - enzymology</topic><topic>NADPH Oxidases - metabolism</topic><topic>nef Gene Products, Human Immunodeficiency Virus</topic><topic>Oncogene Proteins - physiology</topic><topic>Phagocytes - enzymology</topic><topic>Protein Subunits</topic><topic>Proto-Oncogene Proteins c-vav</topic><topic>rac1 GTP-Binding Protein - physiology</topic><topic>src Homology Domains</topic><topic>Superoxides - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vilhardt, Frederik</creatorcontrib><creatorcontrib>Plastre, Olivier</creatorcontrib><creatorcontrib>Sawada, Makoto</creatorcontrib><creatorcontrib>Suzuki, Kazuo</creatorcontrib><creatorcontrib>Wiznerowicz, Maciej</creatorcontrib><creatorcontrib>Kiyokawa, Etsuko</creatorcontrib><creatorcontrib>Trono, Didier</creatorcontrib><creatorcontrib>Krause, Karl-Heinz</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vilhardt, Frederik</au><au>Plastre, Olivier</au><au>Sawada, Makoto</au><au>Suzuki, Kazuo</au><au>Wiznerowicz, Maciej</au><au>Kiyokawa, Etsuko</au><au>Trono, Didier</au><au>Krause, Karl-Heinz</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The HIV-1 Nef Protein and Phagocyte NADPH Oxidase Activation</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2002-11-01</date><risdate>2002</risdate><volume>277</volume><issue>44</issue><spage>42136</spage><epage>42143</epage><pages>42136-42143</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Nef, a multifunctional HIV protein, activates the Vav/Rac/p21-activated kinase (PAK) signaling pathway. Given the potential
role of this pathway in the activation of the phagocyte NADPH oxidase, we have investigated the effect of the HIV-1 Nef protein
on the phagocyte respiratory burst. Microglia (cell line and primary culture) were transduced with lentiviral expression vectors.
Expression of Nef did not activate the NADPH oxidase by itself but led to a massive enhancement of the responses to a variety
of stimuli (Ca 2+ ionophore, formyl peptide, endotoxin). These effects were not caused by up-regulation of phagocyte NADPH oxidase subunits.
Nef mutants lacking motifs involved in the interaction with Vav and PAK failed to reproduce the effects of wild type Nef,
suggesting a role for the Vav/Rac/PAK signaling pathway. The following results suggest a key role for Rac in the priming effect
of Nef. (i) Inactivation of Rac by Clostridium difficile toxin B abolished the Nef effect. (ii) The fraction of activated Rac1 was increased in Nef-transduced cells, and (iii) the
dominant positive Rac1(V12) mutant mimicked the effect of Nef. These results are to our knowledge the first analysis of the
effect of Rac activation on the NADPH oxidase in intact phagocytes. Rac activation is not sufficient to stimulate the phagocyte
NADPH oxidase; however, it markedly enhances the NADPH oxidase response to other stimuli.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>12207012</pmid><doi>10.1074/jbc.M200862200</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acid Motifs Animals Cell Line Enzyme Activation Gene Products, nef - physiology HIV-1 - physiology Mice Microglia - enzymology NADPH Oxidases - metabolism nef Gene Products, Human Immunodeficiency Virus Oncogene Proteins - physiology Phagocytes - enzymology Protein Subunits Proto-Oncogene Proteins c-vav rac1 GTP-Binding Protein - physiology src Homology Domains Superoxides - metabolism |
| title | The HIV-1 Nef Protein and Phagocyte NADPH Oxidase Activation |
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