Heat Shock Protein 75 (TRAP1) Antagonizes Reactive Oxygen Species Generation and Protects Cells from Granzyme M-mediated Apoptosis
Natural killer (NK) cells play an important role in innate immunity against virally infected or transformed cells as the first defense line. Granzyme M (GzmM) is an orphan granzyme that is constitutively highly expressed in NK cells and is consistent with NK cell-mediated cytolysis. We recently demo...
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| Veröffentlicht in: | The Journal of biological chemistry 2007-07, Vol.282 (28), p.20553-20560 |
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| creator | Hua, Guoqiang Zhang, Qixiang Fan, Zusen |
| description | Natural killer (NK) cells play an important role in innate immunity against virally infected or transformed cells as the first defense line. Granzyme M (GzmM) is an orphan granzyme that is constitutively highly expressed in NK cells and is consistent with NK cell-mediated cytolysis. We recently demonstrated that GzmM induces caspase-dependent apoptosis with DNA fragmentation through direct cleavage of inhibitor of caspase-activated DNase (ICAD). However, the molecular mechanisms for GzmM-induced apoptosis are unclear. We found GzmM causes mitochondrial swelling and loss of mitochondrial transmembrane potential. Moreover, GzmM initiates reactive oxygen species (ROS) generation and cytochrome c release. Heat shock protein 75 (HSP75, also known as TRAP1) acts as an antagonist of ROS and protects cells from GzmM-mediated apoptosis. GzmM cleaves TRAP1 and abolishes its antagonistic function to ROS, resulting in ROS accumulation. Silencing TRAP1 through RNA interference increases ROS accumulation, whereas TRAP1 overexpression attenuates ROS production. ROS accumulation is in accordance with the release of cytochrome c from mitochondria and enhances GzmM-mediated apoptosis. |
| doi_str_mv | 10.1074/jbc.M703196200 |
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Granzyme M (GzmM) is an orphan granzyme that is constitutively highly expressed in NK cells and is consistent with NK cell-mediated cytolysis. We recently demonstrated that GzmM induces caspase-dependent apoptosis with DNA fragmentation through direct cleavage of inhibitor of caspase-activated DNase (ICAD). However, the molecular mechanisms for GzmM-induced apoptosis are unclear. We found GzmM causes mitochondrial swelling and loss of mitochondrial transmembrane potential. Moreover, GzmM initiates reactive oxygen species (ROS) generation and cytochrome c release. Heat shock protein 75 (HSP75, also known as TRAP1) acts as an antagonist of ROS and protects cells from GzmM-mediated apoptosis. GzmM cleaves TRAP1 and abolishes its antagonistic function to ROS, resulting in ROS accumulation. Silencing TRAP1 through RNA interference increases ROS accumulation, whereas TRAP1 overexpression attenuates ROS production. ROS accumulation is in accordance with the release of cytochrome c from mitochondria and enhances GzmM-mediated apoptosis.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M703196200</identifier><identifier>PMID: 17513296</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Apoptosis - genetics ; Apoptosis - immunology ; Caspases - genetics ; Caspases - immunology ; Caspases - metabolism ; Cytochromes c - genetics ; Cytochromes c - immunology ; Cytochromes c - metabolism ; DNA Fragmentation ; Granzymes - genetics ; Granzymes - immunology ; Granzymes - metabolism ; HeLa Cells ; HSP90 Heat-Shock Proteins - genetics ; HSP90 Heat-Shock Proteins - immunology ; HSP90 Heat-Shock Proteins - metabolism ; Humans ; Immunity, Innate - genetics ; Killer Cells, Natural - immunology ; Killer Cells, Natural - metabolism ; Membrane Potential, Mitochondrial - genetics ; Membrane Potential, Mitochondrial - immunology ; Mitochondria - genetics ; Mitochondria - immunology ; Mitochondria - microbiology ; Reactive Oxygen Species - antagonists & inhibitors ; Reactive Oxygen Species - immunology ; Reactive Oxygen Species - metabolism ; RNA Interference ; Virus Diseases - genetics ; Virus Diseases - immunology ; Virus Diseases - metabolism</subject><ispartof>The Journal of biological chemistry, 2007-07, Vol.282 (28), p.20553-20560</ispartof><rights>2007 © 2007 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c553t-5f26904bf83bb264fd222e658df9631fd7599db0b48043e64983f07d79a0ebdf3</citedby><cites>FETCH-LOGICAL-c553t-5f26904bf83bb264fd222e658df9631fd7599db0b48043e64983f07d79a0ebdf3</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/17513296$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hua, Guoqiang</creatorcontrib><creatorcontrib>Zhang, Qixiang</creatorcontrib><creatorcontrib>Fan, Zusen</creatorcontrib><title>Heat Shock Protein 75 (TRAP1) Antagonizes Reactive Oxygen Species Generation and Protects Cells from Granzyme M-mediated Apoptosis</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Natural killer (NK) cells play an important role in innate immunity against virally infected or transformed cells as the first defense line. Granzyme M (GzmM) is an orphan granzyme that is constitutively highly expressed in NK cells and is consistent with NK cell-mediated cytolysis. We recently demonstrated that GzmM induces caspase-dependent apoptosis with DNA fragmentation through direct cleavage of inhibitor of caspase-activated DNase (ICAD). However, the molecular mechanisms for GzmM-induced apoptosis are unclear. We found GzmM causes mitochondrial swelling and loss of mitochondrial transmembrane potential. Moreover, GzmM initiates reactive oxygen species (ROS) generation and cytochrome c release. Heat shock protein 75 (HSP75, also known as TRAP1) acts as an antagonist of ROS and protects cells from GzmM-mediated apoptosis. GzmM cleaves TRAP1 and abolishes its antagonistic function to ROS, resulting in ROS accumulation. Silencing TRAP1 through RNA interference increases ROS accumulation, whereas TRAP1 overexpression attenuates ROS production. ROS accumulation is in accordance with the release of cytochrome c from mitochondria and enhances GzmM-mediated apoptosis.</description><subject>Apoptosis - genetics</subject><subject>Apoptosis - immunology</subject><subject>Caspases - genetics</subject><subject>Caspases - immunology</subject><subject>Caspases - metabolism</subject><subject>Cytochromes c - genetics</subject><subject>Cytochromes c - immunology</subject><subject>Cytochromes c - metabolism</subject><subject>DNA Fragmentation</subject><subject>Granzymes - genetics</subject><subject>Granzymes - immunology</subject><subject>Granzymes - metabolism</subject><subject>HeLa Cells</subject><subject>HSP90 Heat-Shock Proteins - genetics</subject><subject>HSP90 Heat-Shock Proteins - immunology</subject><subject>HSP90 Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Immunity, Innate - genetics</subject><subject>Killer Cells, Natural - immunology</subject><subject>Killer Cells, Natural - metabolism</subject><subject>Membrane Potential, Mitochondrial - genetics</subject><subject>Membrane Potential, Mitochondrial - immunology</subject><subject>Mitochondria - genetics</subject><subject>Mitochondria - immunology</subject><subject>Mitochondria - microbiology</subject><subject>Reactive Oxygen Species - antagonists & inhibitors</subject><subject>Reactive Oxygen Species - immunology</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>RNA Interference</subject><subject>Virus Diseases - genetics</subject><subject>Virus Diseases - immunology</subject><subject>Virus Diseases - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kM9rFDEUx4Modq1ePUoOInqYNT8mM5PjsuhWaGlpK3gLmeRlN3VnMibZ6vboX250F3oyEAKPT77vvQ9CrymZU9LWH-96M79oCaeyYYQ8QTNKOl5xQb89RTNCGK0kE90JepHSHSmnlvQ5OqGtoJzJZoZ-n4HO-GYTzHd8FUMGP-JW4Pe314sr-gEvxqzXYfQPkPA1aJP9PeDLX_s1jPhmAuNLfQUjRJ19GLEe7SHF5ISXsN0m7GIY8Crq8WE_AL6oBrBeZ7B4MYUph-TTS_TM6W2CV8f3FH39_Ol2eVadX66-LBfnlRGC50o41khS967jfc-a2lnGGDSis042nDrbCiltT_q6IzWHppYdd6S1rdQEeuv4KXp3yJ1i-LGDlNXgkylD6hHCLikqu6ahghdwfgBNDClFcGqKftBxryhRf62rYl09Wi8f3hyTd33Z7xE_ai7A2wOw8evNTx9B9T6YDQyKdaxcxYj417g7YFA03HuIKhXDoynKYlGqbPD_G-EPeSScMw</recordid><startdate>20070713</startdate><enddate>20070713</enddate><creator>Hua, Guoqiang</creator><creator>Zhang, Qixiang</creator><creator>Fan, Zusen</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>7T5</scope><scope>7U9</scope><scope>H94</scope></search><sort><creationdate>20070713</creationdate><title>Heat Shock Protein 75 (TRAP1) Antagonizes Reactive Oxygen Species Generation and Protects Cells from Granzyme M-mediated Apoptosis</title><author>Hua, Guoqiang ; Zhang, Qixiang ; Fan, Zusen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c553t-5f26904bf83bb264fd222e658df9631fd7599db0b48043e64983f07d79a0ebdf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Apoptosis - genetics</topic><topic>Apoptosis - immunology</topic><topic>Caspases - genetics</topic><topic>Caspases - immunology</topic><topic>Caspases - metabolism</topic><topic>Cytochromes c - genetics</topic><topic>Cytochromes c - immunology</topic><topic>Cytochromes c - metabolism</topic><topic>DNA Fragmentation</topic><topic>Granzymes - genetics</topic><topic>Granzymes - immunology</topic><topic>Granzymes - metabolism</topic><topic>HeLa Cells</topic><topic>HSP90 Heat-Shock Proteins - genetics</topic><topic>HSP90 Heat-Shock Proteins - immunology</topic><topic>HSP90 Heat-Shock Proteins - metabolism</topic><topic>Humans</topic><topic>Immunity, Innate - genetics</topic><topic>Killer Cells, Natural - immunology</topic><topic>Killer Cells, Natural - metabolism</topic><topic>Membrane Potential, Mitochondrial - genetics</topic><topic>Membrane Potential, Mitochondrial - immunology</topic><topic>Mitochondria - genetics</topic><topic>Mitochondria - immunology</topic><topic>Mitochondria - microbiology</topic><topic>Reactive Oxygen Species - antagonists & inhibitors</topic><topic>Reactive Oxygen Species - immunology</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>RNA Interference</topic><topic>Virus Diseases - genetics</topic><topic>Virus Diseases - immunology</topic><topic>Virus Diseases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hua, Guoqiang</creatorcontrib><creatorcontrib>Zhang, Qixiang</creatorcontrib><creatorcontrib>Fan, Zusen</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>Immunology Abstracts</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>Hua, Guoqiang</au><au>Zhang, Qixiang</au><au>Fan, Zusen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Heat Shock Protein 75 (TRAP1) Antagonizes Reactive Oxygen Species Generation and Protects Cells from Granzyme M-mediated Apoptosis</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2007-07-13</date><risdate>2007</risdate><volume>282</volume><issue>28</issue><spage>20553</spage><epage>20560</epage><pages>20553-20560</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Natural killer (NK) cells play an important role in innate immunity against virally infected or transformed cells as the first defense line. Granzyme M (GzmM) is an orphan granzyme that is constitutively highly expressed in NK cells and is consistent with NK cell-mediated cytolysis. We recently demonstrated that GzmM induces caspase-dependent apoptosis with DNA fragmentation through direct cleavage of inhibitor of caspase-activated DNase (ICAD). However, the molecular mechanisms for GzmM-induced apoptosis are unclear. We found GzmM causes mitochondrial swelling and loss of mitochondrial transmembrane potential. Moreover, GzmM initiates reactive oxygen species (ROS) generation and cytochrome c release. Heat shock protein 75 (HSP75, also known as TRAP1) acts as an antagonist of ROS and protects cells from GzmM-mediated apoptosis. GzmM cleaves TRAP1 and abolishes its antagonistic function to ROS, resulting in ROS accumulation. Silencing TRAP1 through RNA interference increases ROS accumulation, whereas TRAP1 overexpression attenuates ROS production. 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| subjects | Apoptosis - genetics Apoptosis - immunology Caspases - genetics Caspases - immunology Caspases - metabolism Cytochromes c - genetics Cytochromes c - immunology Cytochromes c - metabolism DNA Fragmentation Granzymes - genetics Granzymes - immunology Granzymes - metabolism HeLa Cells HSP90 Heat-Shock Proteins - genetics HSP90 Heat-Shock Proteins - immunology HSP90 Heat-Shock Proteins - metabolism Humans Immunity, Innate - genetics Killer Cells, Natural - immunology Killer Cells, Natural - metabolism Membrane Potential, Mitochondrial - genetics Membrane Potential, Mitochondrial - immunology Mitochondria - genetics Mitochondria - immunology Mitochondria - microbiology Reactive Oxygen Species - antagonists & inhibitors Reactive Oxygen Species - immunology Reactive Oxygen Species - metabolism RNA Interference Virus Diseases - genetics Virus Diseases - immunology Virus Diseases - metabolism |
| title | Heat Shock Protein 75 (TRAP1) Antagonizes Reactive Oxygen Species Generation and Protects Cells from Granzyme M-mediated Apoptosis |
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