Granzyme B Encoded by the Commonly Occurring Human RAH Allele Retains Pro-apoptotic Activity
A key function of human granzyme B (GrB) is to induce apoptosis of target cells in conjunction with perforin. The RAH allele is the first documented variant of the human GrB gene, occurs at a frequency of 25–30%, and encodes three amino acid substitutions (Q48R, P88A, and Y245H). It was initially re...
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| Veröffentlicht in: | The Journal of biological chemistry 2004-04, Vol.279 (17), p.16907-16911 |
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| container_issue | 17 |
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| container_title | The Journal of biological chemistry |
| container_volume | 279 |
| creator | Sun, Jiuru Bird, Catherina H. Thia, Kevin Y. Matthews, Antony Y. Trapani, Joseph A. Bird, Phillip I. |
| description | A key function of human granzyme B (GrB) is to induce apoptosis of target cells in conjunction with perforin. The RAH allele is the first documented variant of the human GrB gene, occurs at a frequency of 25–30%, and encodes three amino acid substitutions (Q48R, P88A, and Y245H). It was initially reported that RAH GrB is incapable of inducing apoptosis, but here we show that it has essentially identical proteolytic and cytotoxic properties to wild type GrB. Recombinant RAH and wild type GrB cleave peptide substrates with similar kinetics, are both capable of cleaving Bid and procaspase 3, and are equally inhibited by proteinase inhibitor 9, an endogenous regulator of GrB. Furthermore, cytotoxic lymphocytes from RAH heterozygotes and homozygotes have no defect in target cell killing, and in vitro RAH GrB and wild type GrB kill cells equally well in the presence of perforin. We conclude that the RAH allele represents a neutral polymorphism in the GrB gene. |
| doi_str_mv | 10.1074/jbc.M400563200 |
| format | Article |
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The RAH allele is the first documented variant of the human GrB gene, occurs at a frequency of 25–30%, and encodes three amino acid substitutions (Q48R, P88A, and Y245H). It was initially reported that RAH GrB is incapable of inducing apoptosis, but here we show that it has essentially identical proteolytic and cytotoxic properties to wild type GrB. Recombinant RAH and wild type GrB cleave peptide substrates with similar kinetics, are both capable of cleaving Bid and procaspase 3, and are equally inhibited by proteinase inhibitor 9, an endogenous regulator of GrB. Furthermore, cytotoxic lymphocytes from RAH heterozygotes and homozygotes have no defect in target cell killing, and in vitro RAH GrB and wild type GrB kill cells equally well in the presence of perforin. We conclude that the RAH allele represents a neutral polymorphism in the GrB gene.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M400563200</identifier><identifier>PMID: 14752093</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alleles ; Amino Acids ; Animals ; Apoptosis ; BH3 Interacting Domain Death Agonist Protein ; Carrier Proteins - chemistry ; Caspase 3 ; Caspases - metabolism ; Dose-Response Relationship, Drug ; Granzymes ; Heterozygote ; Homozygote ; Humans ; K562 Cells ; Killer Cells, Lymphokine-Activated - metabolism ; Kinetics ; Lymphocytes - metabolism ; Mice ; Pichia - metabolism ; Polymorphism, Genetic ; Polymorphism, Single-Stranded Conformational ; Protease Inhibitors - pharmacology ; Recombinant Proteins - chemistry ; Serine Endopeptidases - biosynthesis ; Serine Endopeptidases - genetics ; Time Factors</subject><ispartof>The Journal of biological chemistry, 2004-04, Vol.279 (17), p.16907-16911</ispartof><rights>2004 © 2004 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-c506t-4b6495ef79a3bb401cfff0d400a0a0a20283143d89e7f33501686a6a8b3824443</citedby><cites>FETCH-LOGICAL-c506t-4b6495ef79a3bb401cfff0d400a0a0a20283143d89e7f33501686a6a8b3824443</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14752093$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Jiuru</creatorcontrib><creatorcontrib>Bird, Catherina H.</creatorcontrib><creatorcontrib>Thia, Kevin Y.</creatorcontrib><creatorcontrib>Matthews, Antony Y.</creatorcontrib><creatorcontrib>Trapani, Joseph A.</creatorcontrib><creatorcontrib>Bird, Phillip I.</creatorcontrib><title>Granzyme B Encoded by the Commonly Occurring Human RAH Allele Retains Pro-apoptotic Activity</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>A key function of human granzyme B (GrB) is to induce apoptosis of target cells in conjunction with perforin. The RAH allele is the first documented variant of the human GrB gene, occurs at a frequency of 25–30%, and encodes three amino acid substitutions (Q48R, P88A, and Y245H). It was initially reported that RAH GrB is incapable of inducing apoptosis, but here we show that it has essentially identical proteolytic and cytotoxic properties to wild type GrB. Recombinant RAH and wild type GrB cleave peptide substrates with similar kinetics, are both capable of cleaving Bid and procaspase 3, and are equally inhibited by proteinase inhibitor 9, an endogenous regulator of GrB. Furthermore, cytotoxic lymphocytes from RAH heterozygotes and homozygotes have no defect in target cell killing, and in vitro RAH GrB and wild type GrB kill cells equally well in the presence of perforin. We conclude that the RAH allele represents a neutral polymorphism in the GrB gene.</description><subject>Alleles</subject><subject>Amino Acids</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>BH3 Interacting Domain Death Agonist Protein</subject><subject>Carrier Proteins - chemistry</subject><subject>Caspase 3</subject><subject>Caspases - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Granzymes</subject><subject>Heterozygote</subject><subject>Homozygote</subject><subject>Humans</subject><subject>K562 Cells</subject><subject>Killer Cells, Lymphokine-Activated - metabolism</subject><subject>Kinetics</subject><subject>Lymphocytes - metabolism</subject><subject>Mice</subject><subject>Pichia - metabolism</subject><subject>Polymorphism, Genetic</subject><subject>Polymorphism, Single-Stranded Conformational</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Recombinant Proteins - chemistry</subject><subject>Serine Endopeptidases - biosynthesis</subject><subject>Serine Endopeptidases - genetics</subject><subject>Time Factors</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kEtv1DAQgC0EokvhyhH5gLhlGT_y8HFZlS5SUVEFEgcky3EmXVdJvNhOUfj1eLUr9cTMYS7fvD5C3jJYM6jlx4fWrr9KgLISHOAZWTFoRCFK9vM5WQFwViheNhfkVYwPkEMq9pJcMFmXHJRYkV_XwUx_lxHpJ3o1Wd9hR9uFpj3SrR9HPw0LvbV2DsFN93Q3j2aid5sd3QwDDkjvMBk3Rfot-MIc_CH55Czd2OQeXVpekxe9GSK-OddL8uPz1fftrri5vf6y3dwUtoQqFbKtpCqxr5URbSuB2b7voctfmWNy4I1gUnSNwroXogRWNZWpTNOKhkspxSX5cJp7CP73jDHp0UWLw2Am9HPUrFYVB3YE1yfQBh9jwF4fghtNWDQDffSps0_95DM3vDtPntsRuyf8LDAD70_A3t3v_7iAunXe7nHUvFZ5sWaVgjpjzQnDrOHRYdDROpwsdrnFJt15978T_gEVyY4A</recordid><startdate>20040423</startdate><enddate>20040423</enddate><creator>Sun, Jiuru</creator><creator>Bird, Catherina H.</creator><creator>Thia, Kevin Y.</creator><creator>Matthews, Antony Y.</creator><creator>Trapani, Joseph A.</creator><creator>Bird, Phillip I.</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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20040423</creationdate><title>Granzyme B Encoded by the Commonly Occurring Human RAH Allele Retains Pro-apoptotic Activity</title><author>Sun, Jiuru ; Bird, Catherina H. ; Thia, Kevin Y. ; Matthews, Antony Y. ; Trapani, Joseph A. ; Bird, Phillip I.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c506t-4b6495ef79a3bb401cfff0d400a0a0a20283143d89e7f33501686a6a8b3824443</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Alleles</topic><topic>Amino Acids</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>BH3 Interacting Domain Death Agonist Protein</topic><topic>Carrier Proteins - chemistry</topic><topic>Caspase 3</topic><topic>Caspases - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Granzymes</topic><topic>Heterozygote</topic><topic>Homozygote</topic><topic>Humans</topic><topic>K562 Cells</topic><topic>Killer Cells, Lymphokine-Activated - metabolism</topic><topic>Kinetics</topic><topic>Lymphocytes - metabolism</topic><topic>Mice</topic><topic>Pichia - metabolism</topic><topic>Polymorphism, Genetic</topic><topic>Polymorphism, Single-Stranded Conformational</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Recombinant Proteins - chemistry</topic><topic>Serine Endopeptidases - biosynthesis</topic><topic>Serine Endopeptidases - genetics</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Jiuru</creatorcontrib><creatorcontrib>Bird, Catherina H.</creatorcontrib><creatorcontrib>Thia, Kevin Y.</creatorcontrib><creatorcontrib>Matthews, Antony Y.</creatorcontrib><creatorcontrib>Trapani, Joseph A.</creatorcontrib><creatorcontrib>Bird, Phillip I.</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>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Jiuru</au><au>Bird, Catherina H.</au><au>Thia, Kevin Y.</au><au>Matthews, Antony Y.</au><au>Trapani, Joseph A.</au><au>Bird, Phillip I.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Granzyme B Encoded by the Commonly Occurring Human RAH Allele Retains Pro-apoptotic Activity</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2004-04-23</date><risdate>2004</risdate><volume>279</volume><issue>17</issue><spage>16907</spage><epage>16911</epage><pages>16907-16911</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>A key function of human granzyme B (GrB) is to induce apoptosis of target cells in conjunction with perforin. The RAH allele is the first documented variant of the human GrB gene, occurs at a frequency of 25–30%, and encodes three amino acid substitutions (Q48R, P88A, and Y245H). It was initially reported that RAH GrB is incapable of inducing apoptosis, but here we show that it has essentially identical proteolytic and cytotoxic properties to wild type GrB. Recombinant RAH and wild type GrB cleave peptide substrates with similar kinetics, are both capable of cleaving Bid and procaspase 3, and are equally inhibited by proteinase inhibitor 9, an endogenous regulator of GrB. Furthermore, cytotoxic lymphocytes from RAH heterozygotes and homozygotes have no defect in target cell killing, and in vitro RAH GrB and wild type GrB kill cells equally well in the presence of perforin. 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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Alleles Amino Acids Animals Apoptosis BH3 Interacting Domain Death Agonist Protein Carrier Proteins - chemistry Caspase 3 Caspases - metabolism Dose-Response Relationship, Drug Granzymes Heterozygote Homozygote Humans K562 Cells Killer Cells, Lymphokine-Activated - metabolism Kinetics Lymphocytes - metabolism Mice Pichia - metabolism Polymorphism, Genetic Polymorphism, Single-Stranded Conformational Protease Inhibitors - pharmacology Recombinant Proteins - chemistry Serine Endopeptidases - biosynthesis Serine Endopeptidases - genetics Time Factors |
| title | Granzyme B Encoded by the Commonly Occurring Human RAH Allele Retains Pro-apoptotic Activity |
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