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Judy Lieberman - One of the best experts on this subject based on the ideXlab platform.
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2002. HMG2 interActs with the nucleosome Assembly protein SET And is A tArget of the cytotoxic T-lymphocyte proteAse GrAnzyme
2014Co-Authors: Zusen Fan, Paul J Beresford, Dong Zhang, Judy LiebermanAbstract:The cytotoxic T-lymphocyte proteAse GrAnzyme A induces cAspAse-independent cell deAth in which DNA single-strAnded nicking is observed insteAd of oligonucleosomAl frAgmentAtion. A 270- to 420-kDA endoplAsmic reticulum-AssociAted complex (SET complex) contAining the nucleosome Assembly protein SET, the tumor suppressor pp32, And the bAse excision repAir enzyme APE cAn induce single-strAnded DNA dAmAge in isolAted nuclei in A GrAnzyme A-dependent mAnner. The normAl functions of the SET complex Are unknown, but the functions of its components suggest thAt it is involved in ActivAting trAnscription And DNA repAir. We now find thAt the SET complex contAins DNA binding And bending Activities mediAted by the chromAtin-AssociAted protein HMG2. HMG2 fAcilitAtes Assembly of nucleoprotein higher-order structures by bending And looping DNA or by stAbilizing underwound DNA. HMG2 is in the SET complex And coprecipitAtes with SET. By confocAl microscopy, it is observed thAt cytoplAsmic HMG2 colocAlizes with SET in AssociAtion with the endoplAsmic reticulum, but most nucleAr HMG2 is unAssociAted with SET. This physicAl AssociAtion suggests thAt HMG2 mAy fAcilitAte the nucleosome Assembly, trAnscriptionAl ActivAtion, And DNA repAir functions of SET And/or APE. HMG2, like SET And APE, is A physiologicAlly relevAnt GrAnzyme A substrAte in tArgeted cells. HMG1, however, is not A substrAte. GrAnzyme A cleAvAge After Lys65 in the midst of HMG box A destroys HMG2-mediAted DNA binding And bending functions. GrAnzyme A cleAvAge And functionAl disruption of ke
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isolAtion of cytotoxic t cell And nk grAnules And purificAtion of their effector proteins
Current protocols in pharmacology, 2010Co-Authors: Judy Lieberman, Denis Martinvalet, Michael Walch, Danielle K Jensen, Jerome ThieryAbstract:Killer lymphocytes induce Apoptosis by the releAse of cytotoxic mediAtors from speciAlized secretory lysosomes, cAlled cytotoxic grAnules, into the immunologicAl synApse formed with A cell tArgeted for eliminAtion. Methods Are presented here for isolAting CTL And NK cell cytotoxic grAnules using cell disruption by nitrogen cAvitAtion followed by continuous Percoll density grAdient frActionAtion. Protocols Are Also given for purifying the key cytolytic molecules (perforin, GrAnzyme A, GrAnzyme B, And grAnulysin) from isolAted cytotoxic grAnules by fAst protein liquid chromAtogrAphy. Curr. Protoc. Cell Biol. 47:3.37.1-3.37.29. © 2010 by John Wiley & Sons, Inc. Keywords: cytotoxic grAnules; CTL; NK cells; perforin; GrAnzyme; grAnulysin
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GrAnzyme A ActivAtes Another wAy to die
Immunological Reviews, 2010Co-Authors: Judy LiebermanAbstract:GrAnzyme A (GzmA) is the most AbundAnt serine proteAse in killer cell cytotoxic grAnules. GzmA ActivAtes A novel progrAmed cell deAth pAthwAy thAt begins in the mitochondrion, where cleAvAge of NDUFS3 in electron trAnsport complex I disrupts mitochondriAl metAbolism And generAtes reActive oxygen species (ROS). ROS drives the endoplAsmic reticulum-AssociAted SET complex into the nucleus, where it ActivAtes single-strAnded DNA dAmAge. GzmA Also tArgets other importAnt nucleAr proteins for degrAdAtion, including histones, the lAmins thAt mAintAin the nucleAr envelope, And severAl key DNA dAmAge repAir proteins (Ku70, PARP-1). Cells thAt Are resistAnt to the cAspAses or GzmB by overexpressing bcl-2 fAmily Anti-Apoptotic proteins or cAspAse or GzmB proteAse inhibitors Are sensitive to GzmA. By ActivAting multiple cell deAth pAthwAys, killer cells provide better protection AgAinst A vAriety of intrAcellulAr pAthogens And tumors. GzmA Also hAs proinflAmmAtory Activity; it ActivAtes pro-interleukin-1betA And mAy Also hAve other proinflAmmAtory effects thAt remAin to be elucidAted.
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response GrAnzyme A cell deAth inducing proteAse proinflAmmAtory Agent or both
Blood, 2009Co-Authors: Denis Martinvalet, Michael Walch, Danielle K Jensen, Jerome Thiery, Judy LiebermanAbstract:We recently showed thAt GrAnzyme A (GzmA) cleAves poly(Adenosine 5′-diphosphAte-ribose) polymerAse-1 (PARP-1) to promote cell deAth And inhibit DNA repAir.[1][1] PARP-1 cleAvAge is required for Apoptotic cell deAth, which reduces inflAmmAtion, becAuse scAvenger mAcrophAges phAgocytose Apoptotic
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the cytotoxic t lymphocyte proteAse GrAnzyme A cleAves And inActivAtes poly Adenosine 5 diphosphAte ribose polymerAse 1
Blood, 2009Co-Authors: Pengcheng Zhu, Dipanjan Chowdhury, Dong Zhang, Denis Martinvalet, Ann Schlesinger, Judy LiebermanAbstract:GrAnzyme A (GzmA) in killer cells induces cAspAse-independent progrAmmed cell deAth. In this study, we show thAt GzmA cleAves the DNA dAmAge sensor poly(Adenosine 5′-diphosphAte-ribose) polymerAse-1 (PARP-1) After Lys498 in its AutomodificAtion domAin, sepArAting the DNA binding domAin from the cAtAlytic domAin, which interferes with repAir of GzmA-induced DNA dAmAge And enhAnces susceptibility to GzmA-mediAted deAth. Overexpressing K498A PARP-1 reduces GzmA-mediAted deAth And drives dying cells to necrosis rAther thAn Apoptosis. Conversely, inhibiting or geneticAlly disrupting PARP-1 enhAnces cell vulnerAbility. The N-terminAl GzmA cleAvAge frAgment of PARP-1 Acts As A PARP-1 dominAnt negAtive, binding to DNA And blocking DNA repAir. Disrupting PARP-1, which is Also A cAspAse tArget, is therefore required for efficient Apoptosis by both cAspAse-independent And cAspAse-dependent pAthwAys.
Kimberly Lane - One of the best experts on this subject based on the ideXlab platform.
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hiv specific cytolytic cd4 t cell responses during Acute hiv infection predict diseAse outcome
Science Translational Medicine, 2012Co-Authors: Damien Z. Soghoian, Heiko Jessen, Isaiah Davis, Michael Flanders, Kailan Sierradavidson, Sam Cutler, Thomas Pertel, Srinika Ranasinghe, Madelene Lindqvist, Kimberly LaneAbstract:EArly immunologicAl events during Acute HIV infection Are thought to fundAmentAlly influence long-term diseAse outcome. WhereAs the contribution of HIV-specific CD8 T cell responses to eArly virAl control is well estAblished, the role of HIV-specific CD4 T cell responses in the control of virAl replicAtion After Acute infection is unknown. A growing body of evidence suggests thAt CD4 T cells—besides their helper function—hAve the cApAcity to directly recognize And kill virAlly infected cells. In A longitudinAl study of A cohort of individuAls Acutely infected with HIV, we observed thAt subjects Able to spontAneously control HIV replicAtion in the Absence of AntiretrovirAl therApy showed A significAnt expAnsion of HIV-specific CD4 T cell responses—but not CD8 T cell responses—compAred to subjects who progressed to A high virAl set point ( P = 0.038). MArkedly, this expAnsion occurred before differences in virAl loAd or CD4 T cell count And wAs chArActerized by robust cytolytic Activity And expression of A distinct profile of perforin And GrAnzymes At the eArliest time point. KAplAn-Meier AnAlysis reveAled thAt the emergence of GrAnzyme A + HIV-specific CD4 T cell responses At bAseline wAs highly predictive of slower diseAse progression And clinicAl outcome (AverAge dAys to CD4 T cell count P = 0.001). These dAtA demonstrAte thAt HIV-specific CD4 T cell responses cAn be used during the eArliest phAse of HIV infection As An immunologicAl predictor of subsequent virAl set point And diseAse outcome. Moreover, these dAtA suggest thAt expAnsion of GrAnzyme A + HIV-specific cytolytic CD4 T cell responses eArly during Acute HIV infection contributes substAntiAlly to the control of virAl replicAtion.
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hiv specific cytolytic cd4 t cell responses during Acute hiv infection predict diseAse outcome
Science Translational Medicine, 2012Co-Authors: Damien Z. Soghoian, Heiko Jessen, Isaiah Davis, Michael Flanders, Kailan Sierradavidson, Sam Cutler, Thomas Pertel, Srinika Ranasinghe, Madelene Lindqvist, Kimberly LaneAbstract:EArly immunologicAl events during Acute HIV infection Are thought to fundAmentAlly influence long-term diseAse outcome. WhereAs the contribution of HIV-specific CD8 T cell responses to eArly virAl control is well estAblished, the role of HIV-specific CD4 T cell responses in the control of virAl replicAtion After Acute infection is unknown. A growing body of evidence suggests thAt CD4 T cells-besides their helper function-hAve the cApAcity to directly recognize And kill virAlly infected cells. In A longitudinAl study of A cohort of individuAls Acutely infected with HIV, we observed thAt subjects Able to spontAneously control HIV replicAtion in the Absence of AntiretrovirAl therApy showed A significAnt expAnsion of HIV-specific CD4 T cell responses-but not CD8 T cell responses-compAred to subjects who progressed to A high virAl set point (P = 0.038). MArkedly, this expAnsion occurred before differences in virAl loAd or CD4 T cell count And wAs chArActerized by robust cytolytic Activity And expression of A distinct profile of perforin And GrAnzymes At the eArliest time point. KAplAn-Meier AnAlysis reveAled thAt the emergence of GrAnzyme A(+) HIV-specific CD4 T cell responses At bAseline wAs highly predictive of slower diseAse progression And clinicAl outcome (AverAge dAys to CD4 T cell count <350/μl wAs 575 versus 306, P = 0.001). These dAtA demonstrAte thAt HIV-specific CD4 T cell responses cAn be used during the eArliest phAse of HIV infection As An immunologicAl predictor of subsequent virAl set point And diseAse outcome. Moreover, these dAtA suggest thAt expAnsion of GrAnzyme A(+) HIV-specific cytolytic CD4 T cell responses eArly during Acute HIV infection contributes substAntiAlly to the control of virAl replicAtion.
Damien Z. Soghoian - One of the best experts on this subject based on the ideXlab platform.
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hiv specific cytolytic cd4 t cell responses during Acute hiv infection predict diseAse outcome
Science Translational Medicine, 2012Co-Authors: Damien Z. Soghoian, Heiko Jessen, Isaiah Davis, Michael Flanders, Kailan Sierradavidson, Sam Cutler, Thomas Pertel, Srinika Ranasinghe, Madelene Lindqvist, Kimberly LaneAbstract:EArly immunologicAl events during Acute HIV infection Are thought to fundAmentAlly influence long-term diseAse outcome. WhereAs the contribution of HIV-specific CD8 T cell responses to eArly virAl control is well estAblished, the role of HIV-specific CD4 T cell responses in the control of virAl replicAtion After Acute infection is unknown. A growing body of evidence suggests thAt CD4 T cells—besides their helper function—hAve the cApAcity to directly recognize And kill virAlly infected cells. In A longitudinAl study of A cohort of individuAls Acutely infected with HIV, we observed thAt subjects Able to spontAneously control HIV replicAtion in the Absence of AntiretrovirAl therApy showed A significAnt expAnsion of HIV-specific CD4 T cell responses—but not CD8 T cell responses—compAred to subjects who progressed to A high virAl set point ( P = 0.038). MArkedly, this expAnsion occurred before differences in virAl loAd or CD4 T cell count And wAs chArActerized by robust cytolytic Activity And expression of A distinct profile of perforin And GrAnzymes At the eArliest time point. KAplAn-Meier AnAlysis reveAled thAt the emergence of GrAnzyme A + HIV-specific CD4 T cell responses At bAseline wAs highly predictive of slower diseAse progression And clinicAl outcome (AverAge dAys to CD4 T cell count P = 0.001). These dAtA demonstrAte thAt HIV-specific CD4 T cell responses cAn be used during the eArliest phAse of HIV infection As An immunologicAl predictor of subsequent virAl set point And diseAse outcome. Moreover, these dAtA suggest thAt expAnsion of GrAnzyme A + HIV-specific cytolytic CD4 T cell responses eArly during Acute HIV infection contributes substAntiAlly to the control of virAl replicAtion.
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hiv specific cytolytic cd4 t cell responses during Acute hiv infection predict diseAse outcome
Science Translational Medicine, 2012Co-Authors: Damien Z. Soghoian, Heiko Jessen, Isaiah Davis, Michael Flanders, Kailan Sierradavidson, Sam Cutler, Thomas Pertel, Srinika Ranasinghe, Madelene Lindqvist, Kimberly LaneAbstract:EArly immunologicAl events during Acute HIV infection Are thought to fundAmentAlly influence long-term diseAse outcome. WhereAs the contribution of HIV-specific CD8 T cell responses to eArly virAl control is well estAblished, the role of HIV-specific CD4 T cell responses in the control of virAl replicAtion After Acute infection is unknown. A growing body of evidence suggests thAt CD4 T cells-besides their helper function-hAve the cApAcity to directly recognize And kill virAlly infected cells. In A longitudinAl study of A cohort of individuAls Acutely infected with HIV, we observed thAt subjects Able to spontAneously control HIV replicAtion in the Absence of AntiretrovirAl therApy showed A significAnt expAnsion of HIV-specific CD4 T cell responses-but not CD8 T cell responses-compAred to subjects who progressed to A high virAl set point (P = 0.038). MArkedly, this expAnsion occurred before differences in virAl loAd or CD4 T cell count And wAs chArActerized by robust cytolytic Activity And expression of A distinct profile of perforin And GrAnzymes At the eArliest time point. KAplAn-Meier AnAlysis reveAled thAt the emergence of GrAnzyme A(+) HIV-specific CD4 T cell responses At bAseline wAs highly predictive of slower diseAse progression And clinicAl outcome (AverAge dAys to CD4 T cell count <350/μl wAs 575 versus 306, P = 0.001). These dAtA demonstrAte thAt HIV-specific CD4 T cell responses cAn be used during the eArliest phAse of HIV infection As An immunologicAl predictor of subsequent virAl set point And diseAse outcome. Moreover, these dAtA suggest thAt expAnsion of GrAnzyme A(+) HIV-specific cytolytic CD4 T cell responses eArly during Acute HIV infection contributes substAntiAlly to the control of virAl replicAtion.
Madelene Lindqvist - One of the best experts on this subject based on the ideXlab platform.
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hiv specific cytolytic cd4 t cell responses during Acute hiv infection predict diseAse outcome
Science Translational Medicine, 2012Co-Authors: Damien Z. Soghoian, Heiko Jessen, Isaiah Davis, Michael Flanders, Kailan Sierradavidson, Sam Cutler, Thomas Pertel, Srinika Ranasinghe, Madelene Lindqvist, Kimberly LaneAbstract:EArly immunologicAl events during Acute HIV infection Are thought to fundAmentAlly influence long-term diseAse outcome. WhereAs the contribution of HIV-specific CD8 T cell responses to eArly virAl control is well estAblished, the role of HIV-specific CD4 T cell responses in the control of virAl replicAtion After Acute infection is unknown. A growing body of evidence suggests thAt CD4 T cells—besides their helper function—hAve the cApAcity to directly recognize And kill virAlly infected cells. In A longitudinAl study of A cohort of individuAls Acutely infected with HIV, we observed thAt subjects Able to spontAneously control HIV replicAtion in the Absence of AntiretrovirAl therApy showed A significAnt expAnsion of HIV-specific CD4 T cell responses—but not CD8 T cell responses—compAred to subjects who progressed to A high virAl set point ( P = 0.038). MArkedly, this expAnsion occurred before differences in virAl loAd or CD4 T cell count And wAs chArActerized by robust cytolytic Activity And expression of A distinct profile of perforin And GrAnzymes At the eArliest time point. KAplAn-Meier AnAlysis reveAled thAt the emergence of GrAnzyme A + HIV-specific CD4 T cell responses At bAseline wAs highly predictive of slower diseAse progression And clinicAl outcome (AverAge dAys to CD4 T cell count P = 0.001). These dAtA demonstrAte thAt HIV-specific CD4 T cell responses cAn be used during the eArliest phAse of HIV infection As An immunologicAl predictor of subsequent virAl set point And diseAse outcome. Moreover, these dAtA suggest thAt expAnsion of GrAnzyme A + HIV-specific cytolytic CD4 T cell responses eArly during Acute HIV infection contributes substAntiAlly to the control of virAl replicAtion.
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hiv specific cytolytic cd4 t cell responses during Acute hiv infection predict diseAse outcome
Science Translational Medicine, 2012Co-Authors: Damien Z. Soghoian, Heiko Jessen, Isaiah Davis, Michael Flanders, Kailan Sierradavidson, Sam Cutler, Thomas Pertel, Srinika Ranasinghe, Madelene Lindqvist, Kimberly LaneAbstract:EArly immunologicAl events during Acute HIV infection Are thought to fundAmentAlly influence long-term diseAse outcome. WhereAs the contribution of HIV-specific CD8 T cell responses to eArly virAl control is well estAblished, the role of HIV-specific CD4 T cell responses in the control of virAl replicAtion After Acute infection is unknown. A growing body of evidence suggests thAt CD4 T cells-besides their helper function-hAve the cApAcity to directly recognize And kill virAlly infected cells. In A longitudinAl study of A cohort of individuAls Acutely infected with HIV, we observed thAt subjects Able to spontAneously control HIV replicAtion in the Absence of AntiretrovirAl therApy showed A significAnt expAnsion of HIV-specific CD4 T cell responses-but not CD8 T cell responses-compAred to subjects who progressed to A high virAl set point (P = 0.038). MArkedly, this expAnsion occurred before differences in virAl loAd or CD4 T cell count And wAs chArActerized by robust cytolytic Activity And expression of A distinct profile of perforin And GrAnzymes At the eArliest time point. KAplAn-Meier AnAlysis reveAled thAt the emergence of GrAnzyme A(+) HIV-specific CD4 T cell responses At bAseline wAs highly predictive of slower diseAse progression And clinicAl outcome (AverAge dAys to CD4 T cell count <350/μl wAs 575 versus 306, P = 0.001). These dAtA demonstrAte thAt HIV-specific CD4 T cell responses cAn be used during the eArliest phAse of HIV infection As An immunologicAl predictor of subsequent virAl set point And diseAse outcome. Moreover, these dAtA suggest thAt expAnsion of GrAnzyme A(+) HIV-specific cytolytic CD4 T cell responses eArly during Acute HIV infection contributes substAntiAlly to the control of virAl replicAtion.
Srinika Ranasinghe - One of the best experts on this subject based on the ideXlab platform.
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hiv specific cytolytic cd4 t cell responses during Acute hiv infection predict diseAse outcome
Science Translational Medicine, 2012Co-Authors: Damien Z. Soghoian, Heiko Jessen, Isaiah Davis, Michael Flanders, Kailan Sierradavidson, Sam Cutler, Thomas Pertel, Srinika Ranasinghe, Madelene Lindqvist, Kimberly LaneAbstract:EArly immunologicAl events during Acute HIV infection Are thought to fundAmentAlly influence long-term diseAse outcome. WhereAs the contribution of HIV-specific CD8 T cell responses to eArly virAl control is well estAblished, the role of HIV-specific CD4 T cell responses in the control of virAl replicAtion After Acute infection is unknown. A growing body of evidence suggests thAt CD4 T cells—besides their helper function—hAve the cApAcity to directly recognize And kill virAlly infected cells. In A longitudinAl study of A cohort of individuAls Acutely infected with HIV, we observed thAt subjects Able to spontAneously control HIV replicAtion in the Absence of AntiretrovirAl therApy showed A significAnt expAnsion of HIV-specific CD4 T cell responses—but not CD8 T cell responses—compAred to subjects who progressed to A high virAl set point ( P = 0.038). MArkedly, this expAnsion occurred before differences in virAl loAd or CD4 T cell count And wAs chArActerized by robust cytolytic Activity And expression of A distinct profile of perforin And GrAnzymes At the eArliest time point. KAplAn-Meier AnAlysis reveAled thAt the emergence of GrAnzyme A + HIV-specific CD4 T cell responses At bAseline wAs highly predictive of slower diseAse progression And clinicAl outcome (AverAge dAys to CD4 T cell count P = 0.001). These dAtA demonstrAte thAt HIV-specific CD4 T cell responses cAn be used during the eArliest phAse of HIV infection As An immunologicAl predictor of subsequent virAl set point And diseAse outcome. Moreover, these dAtA suggest thAt expAnsion of GrAnzyme A + HIV-specific cytolytic CD4 T cell responses eArly during Acute HIV infection contributes substAntiAlly to the control of virAl replicAtion.
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hiv specific cytolytic cd4 t cell responses during Acute hiv infection predict diseAse outcome
Science Translational Medicine, 2012Co-Authors: Damien Z. Soghoian, Heiko Jessen, Isaiah Davis, Michael Flanders, Kailan Sierradavidson, Sam Cutler, Thomas Pertel, Srinika Ranasinghe, Madelene Lindqvist, Kimberly LaneAbstract:EArly immunologicAl events during Acute HIV infection Are thought to fundAmentAlly influence long-term diseAse outcome. WhereAs the contribution of HIV-specific CD8 T cell responses to eArly virAl control is well estAblished, the role of HIV-specific CD4 T cell responses in the control of virAl replicAtion After Acute infection is unknown. A growing body of evidence suggests thAt CD4 T cells-besides their helper function-hAve the cApAcity to directly recognize And kill virAlly infected cells. In A longitudinAl study of A cohort of individuAls Acutely infected with HIV, we observed thAt subjects Able to spontAneously control HIV replicAtion in the Absence of AntiretrovirAl therApy showed A significAnt expAnsion of HIV-specific CD4 T cell responses-but not CD8 T cell responses-compAred to subjects who progressed to A high virAl set point (P = 0.038). MArkedly, this expAnsion occurred before differences in virAl loAd or CD4 T cell count And wAs chArActerized by robust cytolytic Activity And expression of A distinct profile of perforin And GrAnzymes At the eArliest time point. KAplAn-Meier AnAlysis reveAled thAt the emergence of GrAnzyme A(+) HIV-specific CD4 T cell responses At bAseline wAs highly predictive of slower diseAse progression And clinicAl outcome (AverAge dAys to CD4 T cell count <350/μl wAs 575 versus 306, P = 0.001). These dAtA demonstrAte thAt HIV-specific CD4 T cell responses cAn be used during the eArliest phAse of HIV infection As An immunologicAl predictor of subsequent virAl set point And diseAse outcome. Moreover, these dAtA suggest thAt expAnsion of GrAnzyme A(+) HIV-specific cytolytic CD4 T cell responses eArly during Acute HIV infection contributes substAntiAlly to the control of virAl replicAtion.
