Mammalian mitochondrial IAP binding proteins

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Abstract

Four mitochondrial proteins have been identified that immunoprecipitate with the mammalian inhibitor of apoptosis (IAP) protein XIAP. Each of them interacts via a processed amino terminus that resembles those of the insect pro-apoptotic IAP binding proteins Grim, HID, Reaper, and Sickle. Two, Diablo/Smac and HrtA2/Omi, have been extensively characterized. Both Diablo and HtrA2 can bind to IAPs and promote apoptosis when over-expressed in transfected cells, but unlike the insect IAP antagonists, to date there is scant evidence that they are important regulators of apoptosis in more physiological circumstances.

Section snippets

Diablo/Smac

Both Diablo and HtrA2 are encoded by nuclear genes. After synthesis the polypeptides are targeted to the mitochondria via classical mitochondrial targeting sequences in their amino termini [32], [33]. These termini are removed to generate novel N-termini that resemble the first few amino acids of the Drosophila IAP antagonists Grim, HID Reaper, and Sickle [39].

Diablo is peculiar amongst the proteins localized to the mitochondria because it does not seem to be highly conserved. Clear homologues

HtrA2/Omi

Unlike Diablo, HtrA2 has clear homologues right down to the bacterial heat-inducible serine protease HtrA/DegP [53], [54], [55]. In bacteria, the role of HtrA is to take care of misfolded proteins either by helping them re-fold or by degrading them. HtrA mutants have reduced survival when grown at high temperatures [56]. The crystal structure of bacterial HtrA reveals it to be a hexamer that interacts with misfolded proteins via its PDZ domains [57], [58]. Human HtrA2 has two PDZ domains, but

Clinical implications

Peptides that mimic the BIR-binding portions of Diablo or HtrA2 are being tested in animal models to determine whether alone or in combination with other agents they can promote apoptosis of tumor cells [61], [66]. For such an approach to be successful, malignant cells, or those treated with chemotherapeutic agents, would have to be dependent on IAP activity for their survival [62]. The IAP antagonists based on the N-termini of Diablo and HtrA2 would kill the cells by antagonizing this IAP

Acknowledgements

D.L.V. is a Scholar of the Leukemia and Lymphoma Society and receives funding from the National Health and Medical Research Council.

References (66)

  • S.L. Wang et al.

    The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID

    Cell

    (1999)
  • C.J. Hawkins et al.

    The Drosophila caspase DRONC cleaves following glutamate or aspartate and is regulated by DIAP1, HID, and GRIM

    J. Biol. Chem.

    (2000)
  • S.M. Srinivasula et al.

    Sickle, a novel Drosophila death gene in the reaper/hid/grim region, encodes an IAP-inhibitory protein

    Curr. Biol.

    (2002)
  • J.P. Wing et al.

    Drosophila sickle is a novel grim-reaper cell death activator

    Curr. Biol.

    (2002)
  • A. Christich et al.

    The damage-responsive Drosophila gene sickle encodes a novel IAP binding protein similar to but distinct from reaper, GRIM, and HID

    Curr. Biol.

    (2002)
  • M. Ditzel et al.

    IAP degradation: decisive blow or altruistic sacrifice?

    Trends Cell Biol.

    (2002)
  • A.M. Verhagen et al.

    Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins

    Cell

    (2000)
  • C.Y. Du et al.

    Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition

    Cell

    (2000)
  • R. Hegde et al.

    Identification of Omi/HtrA-2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein–caspase interaction

    J. Biol. Chem.

    (2002)
  • A.M. Verhagen et al.

    HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins

    J. Biol. Chem.

    (2002)
  • Y. Suzuki et al.

    A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death

    Mol. Cell

    (2001)
  • L.M. Martins et al.

    The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif

    J. Biol. Chem.

    (2002)
  • C.H. Sun et al.

    NMR structure and mutagenesis of the third Bir domain of the inhibitor of apoptosis protein XIAP

    J. Biol. Chem.

    (2000)
  • Y.H. Huang et al.

    Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain

    Cell

    (2001)
  • L. Faccio et al.

    Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia

    J. Biol. Chem.

    (2000)
  • T. Clausen et al.

    The HtrA family of proteases: implications for protein composition and cell fate

    Mol. Cell

    (2002)
  • C. Spiess et al.

    A temperature-dependent switch from chaperone to protease in a widely conserved heat shock protein

    Cell

    (1999)
  • C.L. Day et al.

    HtrA—A renaissance protein

    Structure

    (2002)
  • P.G. Ekert et al.

    Apoptosis, haemopoiesis and leukaemogenesis

    Baillieres Clin. Haematol.

    (1997)
  • C.R. Arnt et al.

    Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ

    J. Biol. Chem.

    (2002)
  • J. Dierlamm et al.

    The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18) (q21;q21) associated with mucosa-associated lymphoid tissue lymphomas

    Blood

    (1999)
  • A.G. Uren et al.

    Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma

    Mol. Cell

    (2000)
  • N.E. Crook et al.

    An apoptosis inhibiting baculovirus gene with a zinc finger like motif

    J. Virol.

    (1993)

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