The apoptosome pathway to caspase activation in primary human Neutrophils exhibits dramatically reduced requirements for cytochrome c

被引:89
作者
Murphy, BM
O'Neill, AJ
Adrain, C
Watson, RWG
Martin, SJ [1 ]
机构
[1] Univ Dublin Trinity Coll, Smurfit Inst, Dept Genet, Mol Cell Biol Lab, Dublin 2, Ireland
[2] Natl Univ Ireland Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin 4, Ireland
[3] Dublin Mol Med Ctr, Dublin 4, Ireland
[4] Mater Misericordiae Univ Hosp, Dept Surg, Dublin 4, Ireland
关键词
apoptosis; XIAP; caspases; cytochrome c; neutrophil;
D O I
10.1084/jem.20021862
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Caspase activation is a central event in numerous forms of apoptosis and results in the proteolytic degradation of multiple substrate proteins that contribute to the apoptotic phenotype. An important route to caspase activation proceeds via assembly of the "apoptosome" as a result of the cell stress-associated release of mitochondrial cytochrome c. Previous studies have shown that primary neutrophils are largely incapable of mitochondrial respiration, suggesting that these cells either lack functional mitochondria or possess a defective respiratory chain. This prompted us to examine whether neutrophils retain an intact cytochrome c/apoptotic protease-activating factor 1 (Apaf-1) pathway to caspase activation and apoptosis. We show that primary human neutrophils contain barely detectable levels of cytochrome c as well as other mitochondrial proteins. Surprisingly, neutrophil cell-free extracts readily supported Apaf-l-dependent caspase activation, suggesting that these cells may assemble cytochrome c-independent apoptosomes. However, further analysis revealed that the trace amount of cytochrome c present in neutrophils is both necessary and sufficient for Apaf-1-dependent caspase activation in these cells. Thus, neutrophils have a lowered threshold requirement for cytochrome c in the Apaf-1-dependent cell death pathway. These observations suggest that neutrophils retain cytochrome c for the purpose of assembling functional apoptosomes rather than for oxidative phosphorylation.
引用
收藏
页码:625 / 632
页数:8
相关论文
共 25 条
  • [11] Granulocyte colony-stimulating factor inhibits the mitochondria-dependent activation of caspase-3 in neutrophils
    Maianski, NA
    Mul, FRJ
    van Buul, JD
    Roos, D
    Kuijpers, TW
    [J]. BLOOD, 2002, 99 (02) : 672 - 679
  • [12] The cytotoxic cell protease granzyme B initiates apoptosis in a cell-free system by proteolytic processing and activation of the ICE/CED-3 family protease, CPP32, via a novel two-step mechanism
    Martin, SJ
    AmaranteMendes, GP
    Shi, LF
    Chuang, TH
    Casiano, CA
    OBrien, GA
    Fitzgerald, P
    Tan, EM
    Bokoch, GM
    Greenberg, AH
    Green, DR
    [J]. EMBO JOURNAL, 1996, 15 (10) : 2407 - 2416
  • [13] Destabilizing influences in apoptosis: sowing the seeds of IAP destruction
    Martin, SJ
    [J]. CELL, 2002, 109 (07) : 793 - 796
  • [14] FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex
    Muzio, M
    Chinnaiyan, AM
    Kischkel, FC
    ORourke, K
    Shevchenko, A
    Ni, J
    Scaffidi, C
    Bretz, JD
    Zhang, M
    Gentz, R
    Mann, M
    Krammer, PH
    Peter, ME
    Dixit, VM
    [J]. CELL, 1996, 85 (06) : 817 - 827
  • [15] Caspase structure, proteolytic substrates, and function during apoptotic cell death
    Nicholson, DW
    [J]. CELL DEATH AND DIFFERENTIATION, 1999, 6 (11) : 1028 - 1042
  • [16] Caspase activation in the absence of mitochondrial changes in granulocyte apoptosis
    Nopp, A
    Lundahl, J
    Stridh, H
    [J]. CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 2002, 128 (02) : 267 - 274
  • [17] Mitochondria in eosinophils: Functional role in apoptosis but not respiration
    Peachman, KK
    Lyles, DS
    Bass, DA
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (04) : 1717 - 1722
  • [18] Expression of genes involved in initiation, regulation, and execution of apoptosis in human neutrophils and during neutrophil differentiation of HL-60 cells
    Santos-Beneit, AM
    Mollinedo, F
    [J]. JOURNAL OF LEUKOCYTE BIOLOGY, 2000, 67 (05) : 712 - 724
  • [19] MACROPHAGE PHAGOCYTOSIS OF AGING NEUTROPHILS IN INFLAMMATION - PROGRAMMED CELL-DEATH IN THE NEUTROPHIL LEADS TO ITS RECOGNITION BY MACROPHAGES
    SAVILL, JS
    WYLLIE, AH
    HENSON, JE
    WALPORT, MJ
    HENSON, PM
    HASLETT, C
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1989, 83 (03) : 865 - 875
  • [20] Ordering the cytochrome c-initiated caspase cascade: Hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner
    Slee, EA
    Harte, MT
    Kluck, RM
    Wolf, BB
    Casiano, CA
    Newmeyer, DD
    Wang, HG
    Reed, JC
    Nicholson, DW
    Alnemri, ES
    Green, DR
    Martin, SJ
    [J]. JOURNAL OF CELL BIOLOGY, 1999, 144 (02) : 281 - 292