Cell death attenuation by 'Usurpin', a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex

Dita M. Rasper, John P. Vaillancourt, Shinji Hadano, Vicky M. Houtzager, Isolde Seiden, Sabina L.C. Keen, Paul Tawa, Steve Xanthoudakis, Jamal Nasir, Duane Martindale, Ben F. Koop, Erin P. Peterson, Nancy A. Thornberry, Jing Qi Huang, David P. MacPherson, Shawn C. Black, Felicita Hornung, Michael J. Lenardo, Michael R. Hayden, Sophie RoyDonald W. Nicholson

    Research output: Contribution to journalArticle

    Abstract

    Apoptotic cell suicide initiated by ligation of CD95 (Fas/APO-1) occurs through recruitment, oligomerization and autocatalytic activation of the cysteine protease, caspase-8 (MACH, FLICE, Mch5). An endogenous mammalian regulator of this process, named Usurpin, has been identified (aliases for Usurpin include CASH, Casper, CLARP, FLAME-1, FLIP, I-FLICE and MRIT). This protein is ubiquitously expressed and exists as at least three isoforms arising by alternative mRNA splicing. The Usurpin gene is comprised of 13 exons and is clustered within approximately 200 Kb with the caspase-8 and -10 genes on human chromosome 2q33-34. The Usurpin polypeptide has features in common with pro-caspase-8 and -10, including tandem 'death effector domains' on the N-terminus of a large subunit/small subunit caspase-like domain, but it lacks key residues that are necessary for caspase proteolytic activity, including the His and Cys which form the catalytic substrates diad, and residues that stabilize the P1 aspartic acid in substrates. Retro-mutation of these residues to functional caspase counterparts failed to restore proteolytic activity, indicating that other determinants also ensure the absence of catalytic potential. Usurpin heterodimerized with pro-caspase-8 in vitro and precluded pro-caspase-8 recruitment by the FADD/MORT1 adapter protein. Cell death induced by CD95 (Fas/APO-1) ligation was attenuated in cells transfected with Usurpin. In vivo, a Usurpin deficit was found in cardiac infarcts where TUNEL-positive myocytes and active caspase-3 expression were prominent following ischemia/reperfusion injury. In contrast, abundant Usurpin expression (and a caspase-3 deficit) occurred in surrounding unaffected cardiac tissue, suggesting reciprocal regulation of these pro- and anti-apoptotic molecules in vivo. Usurpin thus appears to be an endogenous modulator of apoptosis sensitivity in mammalian cells, including the susceptibility of cardiac myocytes to apoptotic death following ischemia/ reperfusion injury.
    Original languageEnglish
    Pages (from-to)271-288
    Number of pages18
    JournalCell Death and Differentiation
    Volume5
    Issue number4
    DOIs
    Publication statusPublished - 1998

    Fingerprint

    Caspase 8
    Caspases
    Cell Death
    Caspase 10
    Reperfusion Injury
    Caspase 3
    Ligation
    Fas-Associated Death Domain Protein
    Cysteine Proteases
    In Situ Nick-End Labeling
    Alternative Splicing
    Human Chromosomes
    Cardiac Myocytes
    Aspartic Acid
    Muscle Cells
    Suicide
    Genes
    Exons
    Protein Isoforms
    Apoptosis

    Keywords

    • Apoptosis
    • CD95 (Fas, APO-1)
    • Caspase
    • Ischemia/reperfusion injury

    Cite this

    Rasper, Dita M. ; Vaillancourt, John P. ; Hadano, Shinji ; Houtzager, Vicky M. ; Seiden, Isolde ; Keen, Sabina L.C. ; Tawa, Paul ; Xanthoudakis, Steve ; Nasir, Jamal ; Martindale, Duane ; Koop, Ben F. ; Peterson, Erin P. ; Thornberry, Nancy A. ; Huang, Jing Qi ; MacPherson, David P. ; Black, Shawn C. ; Hornung, Felicita ; Lenardo, Michael J. ; Hayden, Michael R. ; Roy, Sophie ; Nicholson, Donald W. / Cell death attenuation by 'Usurpin', a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex. In: Cell Death and Differentiation. 1998 ; Vol. 5, No. 4. pp. 271-288.
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    abstract = "Apoptotic cell suicide initiated by ligation of CD95 (Fas/APO-1) occurs through recruitment, oligomerization and autocatalytic activation of the cysteine protease, caspase-8 (MACH, FLICE, Mch5). An endogenous mammalian regulator of this process, named Usurpin, has been identified (aliases for Usurpin include CASH, Casper, CLARP, FLAME-1, FLIP, I-FLICE and MRIT). This protein is ubiquitously expressed and exists as at least three isoforms arising by alternative mRNA splicing. The Usurpin gene is comprised of 13 exons and is clustered within approximately 200 Kb with the caspase-8 and -10 genes on human chromosome 2q33-34. The Usurpin polypeptide has features in common with pro-caspase-8 and -10, including tandem 'death effector domains' on the N-terminus of a large subunit/small subunit caspase-like domain, but it lacks key residues that are necessary for caspase proteolytic activity, including the His and Cys which form the catalytic substrates diad, and residues that stabilize the P1 aspartic acid in substrates. Retro-mutation of these residues to functional caspase counterparts failed to restore proteolytic activity, indicating that other determinants also ensure the absence of catalytic potential. Usurpin heterodimerized with pro-caspase-8 in vitro and precluded pro-caspase-8 recruitment by the FADD/MORT1 adapter protein. Cell death induced by CD95 (Fas/APO-1) ligation was attenuated in cells transfected with Usurpin. In vivo, a Usurpin deficit was found in cardiac infarcts where TUNEL-positive myocytes and active caspase-3 expression were prominent following ischemia/reperfusion injury. In contrast, abundant Usurpin expression (and a caspase-3 deficit) occurred in surrounding unaffected cardiac tissue, suggesting reciprocal regulation of these pro- and anti-apoptotic molecules in vivo. Usurpin thus appears to be an endogenous modulator of apoptosis sensitivity in mammalian cells, including the susceptibility of cardiac myocytes to apoptotic death following ischemia/ reperfusion injury.",
    keywords = "Apoptosis, CD95 (Fas, APO-1), Caspase, Ischemia/reperfusion injury",
    author = "Rasper, {Dita M.} and Vaillancourt, {John P.} and Shinji Hadano and Houtzager, {Vicky M.} and Isolde Seiden and Keen, {Sabina L.C.} and Paul Tawa and Steve Xanthoudakis and Jamal Nasir and Duane Martindale and Koop, {Ben F.} and Peterson, {Erin P.} and Thornberry, {Nancy A.} and Huang, {Jing Qi} and MacPherson, {David P.} and Black, {Shawn C.} and Felicita Hornung and Lenardo, {Michael J.} and Hayden, {Michael R.} and Sophie Roy and Nicholson, {Donald W.}",
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    language = "English",
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    pages = "271--288",
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    Rasper, DM, Vaillancourt, JP, Hadano, S, Houtzager, VM, Seiden, I, Keen, SLC, Tawa, P, Xanthoudakis, S, Nasir, J, Martindale, D, Koop, BF, Peterson, EP, Thornberry, NA, Huang, JQ, MacPherson, DP, Black, SC, Hornung, F, Lenardo, MJ, Hayden, MR, Roy, S & Nicholson, DW 1998, 'Cell death attenuation by 'Usurpin', a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex', Cell Death and Differentiation, vol. 5, no. 4, pp. 271-288. https://doi.org/10.1038/sj.cdd.4400370

    Cell death attenuation by 'Usurpin', a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex. / Rasper, Dita M.; Vaillancourt, John P.; Hadano, Shinji; Houtzager, Vicky M.; Seiden, Isolde; Keen, Sabina L.C.; Tawa, Paul; Xanthoudakis, Steve; Nasir, Jamal; Martindale, Duane; Koop, Ben F.; Peterson, Erin P.; Thornberry, Nancy A.; Huang, Jing Qi; MacPherson, David P.; Black, Shawn C.; Hornung, Felicita; Lenardo, Michael J.; Hayden, Michael R.; Roy, Sophie; Nicholson, Donald W.

    In: Cell Death and Differentiation, Vol. 5, No. 4, 1998, p. 271-288.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Cell death attenuation by 'Usurpin', a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex

    AU - Rasper, Dita M.

    AU - Vaillancourt, John P.

    AU - Hadano, Shinji

    AU - Houtzager, Vicky M.

    AU - Seiden, Isolde

    AU - Keen, Sabina L.C.

    AU - Tawa, Paul

    AU - Xanthoudakis, Steve

    AU - Nasir, Jamal

    AU - Martindale, Duane

    AU - Koop, Ben F.

    AU - Peterson, Erin P.

    AU - Thornberry, Nancy A.

    AU - Huang, Jing Qi

    AU - MacPherson, David P.

    AU - Black, Shawn C.

    AU - Hornung, Felicita

    AU - Lenardo, Michael J.

    AU - Hayden, Michael R.

    AU - Roy, Sophie

    AU - Nicholson, Donald W.

    PY - 1998

    Y1 - 1998

    N2 - Apoptotic cell suicide initiated by ligation of CD95 (Fas/APO-1) occurs through recruitment, oligomerization and autocatalytic activation of the cysteine protease, caspase-8 (MACH, FLICE, Mch5). An endogenous mammalian regulator of this process, named Usurpin, has been identified (aliases for Usurpin include CASH, Casper, CLARP, FLAME-1, FLIP, I-FLICE and MRIT). This protein is ubiquitously expressed and exists as at least three isoforms arising by alternative mRNA splicing. The Usurpin gene is comprised of 13 exons and is clustered within approximately 200 Kb with the caspase-8 and -10 genes on human chromosome 2q33-34. The Usurpin polypeptide has features in common with pro-caspase-8 and -10, including tandem 'death effector domains' on the N-terminus of a large subunit/small subunit caspase-like domain, but it lacks key residues that are necessary for caspase proteolytic activity, including the His and Cys which form the catalytic substrates diad, and residues that stabilize the P1 aspartic acid in substrates. Retro-mutation of these residues to functional caspase counterparts failed to restore proteolytic activity, indicating that other determinants also ensure the absence of catalytic potential. Usurpin heterodimerized with pro-caspase-8 in vitro and precluded pro-caspase-8 recruitment by the FADD/MORT1 adapter protein. Cell death induced by CD95 (Fas/APO-1) ligation was attenuated in cells transfected with Usurpin. In vivo, a Usurpin deficit was found in cardiac infarcts where TUNEL-positive myocytes and active caspase-3 expression were prominent following ischemia/reperfusion injury. In contrast, abundant Usurpin expression (and a caspase-3 deficit) occurred in surrounding unaffected cardiac tissue, suggesting reciprocal regulation of these pro- and anti-apoptotic molecules in vivo. Usurpin thus appears to be an endogenous modulator of apoptosis sensitivity in mammalian cells, including the susceptibility of cardiac myocytes to apoptotic death following ischemia/ reperfusion injury.

    AB - Apoptotic cell suicide initiated by ligation of CD95 (Fas/APO-1) occurs through recruitment, oligomerization and autocatalytic activation of the cysteine protease, caspase-8 (MACH, FLICE, Mch5). An endogenous mammalian regulator of this process, named Usurpin, has been identified (aliases for Usurpin include CASH, Casper, CLARP, FLAME-1, FLIP, I-FLICE and MRIT). This protein is ubiquitously expressed and exists as at least three isoforms arising by alternative mRNA splicing. The Usurpin gene is comprised of 13 exons and is clustered within approximately 200 Kb with the caspase-8 and -10 genes on human chromosome 2q33-34. The Usurpin polypeptide has features in common with pro-caspase-8 and -10, including tandem 'death effector domains' on the N-terminus of a large subunit/small subunit caspase-like domain, but it lacks key residues that are necessary for caspase proteolytic activity, including the His and Cys which form the catalytic substrates diad, and residues that stabilize the P1 aspartic acid in substrates. Retro-mutation of these residues to functional caspase counterparts failed to restore proteolytic activity, indicating that other determinants also ensure the absence of catalytic potential. Usurpin heterodimerized with pro-caspase-8 in vitro and precluded pro-caspase-8 recruitment by the FADD/MORT1 adapter protein. Cell death induced by CD95 (Fas/APO-1) ligation was attenuated in cells transfected with Usurpin. In vivo, a Usurpin deficit was found in cardiac infarcts where TUNEL-positive myocytes and active caspase-3 expression were prominent following ischemia/reperfusion injury. In contrast, abundant Usurpin expression (and a caspase-3 deficit) occurred in surrounding unaffected cardiac tissue, suggesting reciprocal regulation of these pro- and anti-apoptotic molecules in vivo. Usurpin thus appears to be an endogenous modulator of apoptosis sensitivity in mammalian cells, including the susceptibility of cardiac myocytes to apoptotic death following ischemia/ reperfusion injury.

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