Apoptosis and survival - Role of IAP-proteins in apoptosis

Role of IAP-proteins in apoptosis

Apoptotic response is activated through either the intrinsic or the extrinsic pathway, depending on the origin of the death stimuli.

The extrinsic pathway is initiated by death receptors, such as FasR (TNF receptor superfamily, member 6) and TNFR1 (tumor necrosis factor receptor superfamily, member 1A). Activation of the FasR and TNFR1 by its cognate ligand results in the recruitment and activation of pro-caspase-8 (caspase-8). Active caspase-8 subsequently cleaves and activates pro-caspase-3 (caspase-3) and pro-caspase-7 (caspase-7). Activation of caspase-3 leads to the ultimate demise of the cell. Caspase-8 and caspase-9 are often referred to as initiator caspases, whereas caspase-3 and caspase-7 are considered as effector caspases [1].

The intrinsic, or mitochondrial apoptotic pathway is activated under stress and by some developmental apoptotic triggers. This pathway is thought to be triggered by translocation of proteins from the pro-apoptotic Bcl-2 family member, such as Bax, into the mitochondria. This event triggers the release of mitochondrial proteins, such as cytochrome c, Smac/DIABLO and Omi/HtrA2 (high-temperature requirement protein A2), and some others [1].

Bax pemeabilization of mitochondria also induces release of Apoptosis-inducing factor, mitochondrion-associated 1 (Aif), which translocates to the nucleus and induces DNA fragmentation in a caspase-independent manner [2].

The extrinsic pathway crosstalks to the intrinsic pathway via caspase-8-mediated cleavage of Bid (a BH3-ONLY member of the BCL2 FAMILY of proteins). After cleavage by caspase-8, tBid translocates to the mitochondrion and triggers the intrinsic pathway [3].

Thereby, the mitochondrial pathway serves as an amplification loop caspases. This amplification occur by two pathways - via activation of caspase-9 and via inhibition of baculoviral IAP repeat-containing proteins (IAPs).

Following its release from mitochondria, cytochrome c binds to and activates protein Apaf-1 in the cytoplasm, followed by binding of Apaf-1 to ATP/dATP and to formation of the apoptosome. Apoptosome mediates activation of caspase-9, thereby triggering a cascade of caspase activation [1].

The baculoviral IAP repeat-containing proteins (IAPs) (XIAP, c-IAP1, c-IAP2, NAIP and survivin) inhibit certain caspases (caspase-3, caspase-7 and caspase-9) by direct binding or by ubiquitylation. Mitochondrial protein Smac/DIABLO, on its release from mitochondria, binds XIAP, c-IAP1, c-IAP2, and survivin in a manner that displaces caspases. So, Smac/DIABLO is a negative regulator of IAPs, and is therefore an apoptosis-enhancing molecule [4].

Cleavage of caspase-9 is not required for activation but is necessary for inactivation of caspase-9 by XIAP. XIAP sequesters caspase-9 in a monomeric state, which serves to prevent catalytic activity [5].

XIAP regulates activity of Aif during apoptosis by its ubiquitination [6].

Serine protease HtrA2/OMI also inhibits IAP-proteins by binding or by cleavage [3].

Peptides derived from the C termini of human Presenilins modulate the protease and apoptotic activities of Omi/HtrA2 by binding to its PDZ domain [7].

In response to cell death stimulation, survivin associates with XIAP via conserved baculovirus IAP repeats. Formation of a survivin-XIAP complex promotes increased XIAP stability against ubiquitination/proteasomal destruction and synergistic inhibition of apoptosis [8].

However, XIAP itself can be a target for caspases and that cleavage destroys its antiapoptotic function [9].

Apoptosis couples to surveillance mechanisms and survivin is a candidate molecule for the interface between apoptosis and cell cycle. Survivin selectively expressed at G₂/M and localized to mitotic spindle microtubules. Survivin as a mitotic substrate of CDK1-cyclin B1 and survivin phosphorylation on Thr³⁴ was required to interaction with initiator caspase-9 [10].

References:

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   Molecular mechanisms of caspase regulation during apoptosis. Nature reviews. Molecular cell biology 2004 Nov;5(11):897-907
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   Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene 2004 Apr 12;23(16):2785-96
3. Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P
   Toxic proteins released from mitochondria in cell death. Oncogene 2004 Apr 12;23(16):2861-74
4. Salvesen GS, Duckett CS
   IAP proteins: blocking the road to death's door. Nature reviews. Molecular cell biology 2002 Jun;3(6):401-10
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   Mechanism of XIAP-mediated inhibition of caspase-9. Molecular cell 2003 Feb;11(2):519-27
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   Apoptosis-inducing factor is a target for ubiquitination through interaction with XIAP. Molecular and cellular biology 2008 Jan;28(1):237-47
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   The C-terminal tail of presenilin regulates Omi/HtrA2 protease activity. The Journal of biological chemistry 2004 Oct 29;279(44):45844-54
8. Dohi T, Okada K, Xia F, Wilford CE, Samuel T, Welsh K, Marusawa H, Zou H, Armstrong R, Matsuzawa S, Salvesen GS, Reed JC, Altieri DC
   An IAP-IAP complex inhibits apoptosis. The Journal of biological chemistry 2004 Aug 13;279(33):34087-90
9. Levkau B, Garton KJ, Ferri N, Kloke K, Nofer JR, Baba HA, Raines EW, Breithardt G
   xIAP induces cell-cycle arrest and activates nuclear factor-kappaB : new survival pathways disabled by caspase-mediated cleavage during apoptosis of human endothelial cells. Circulation research 2001 Feb 16;88(3):282-90
10. O'Connor DS, Grossman D, Plescia J, Li F, Zhang H, Villa A, Tognin S, Marchisio PC, Altieri DC
    Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proceedings of the National Academy of Sciences of the United States of America 2000 Nov 21;97(24):13103-7