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Apoptosis

IAP proteins: blocking the road to death's door

Abstract

The 'inhibitor of apoptosis' (IAP) gene family, which was discovered less than a decade ago, encodes a group of structurally related proteins that, in addition to their ability to suppress apoptotic cell death, are involved in an increasing number of seemingly unrelated cellular functions. Here, we review the functional and structural properties of this fascinating group of proteins, and of several recently identified IAP-binding factors that regulate IAP function.

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Figure 1: Mammalian IAPs/BIRPs.
Figure 2: The intrinsic and extrinsic cell-death pathways.
Figure 3: Interactions of caspase-3 and caspase-9 with XAIP.
Figure 4: IAP-binding motifs (IBMs).
Figure 5: Association of IAPs with signalling complexes.

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Acknowledgements

We thank the members of our laboratories, and colleagues past and present, for their support and advice, and we are grateful to our collaborators who have given us permission to cite unpublished work. Our apologies to our colleagues whose important contributions have been inadvertently overlooked or cited only indirectly due to space limitations.

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Correspondence to Colin S. Duckett.

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DATABASES

FlyBase

grim

Morgue

rpr

skl

Interpro

BIR

RING domain

LocusLink

Bax

Bid

Fas

Naip1

NRAGE

XAF1

OMIM

acute myelogenous leukaemia

Swiss-Prot

Apaf-1

Bcl-2

caspase-1

caspase-3

caspase-7

caspase 8

caspase-9

c-IAP1

c-IAP2

DIABLO

E1

E2

FADD

MALT1

Omi/Htra2

Smac

survivin

TAB1

TAK1

TRADD

TRAF1

TRAF2

XIAP

Wormbase

BIR-1

CED-4

Glossary

RING

A structural domain that is found in many IAP proteins and shows E3 ubiquitin ligase activity.

CARD

Caspase recruitment domain. A conserved domain that is found in c-IAP1 and c-IAP2. The function of the domain in these molecules is currently unknown.

TNF

(Tumour-necrosis factor). Founding member of a family of pro-inflammatory cytokines that induces apoptosis in various experimental systems.

TNFR2

(Type 2 tumour-necrosis factor receptor). The second receptor identified that can bind TNF.

NAIP

Neuronal apoptosis inhibitory protein. This was the first described cellular IAP.

DISC

Death-inducing signalling complex. The name given to a group of cellular factors that are recruited to the intracellular domain of the cell-surface receptor CD95/Fas/Apo-1 after ligand binding.

NF-κB

Nuclear factor of κB. A widely expressed transcription factor that is activated by cellular stress and can induce the expression of numerous anti-apoptotic genes.

IRES

(Internal ribosomal entry site). Sequence found in the 5′ untranslated sequences of certain viral and cellular genes that allows for cap-independent translation of protein synthesis.

UBIQUITIN

A 76-amino-acid protein that can be covalently attached to specific lysine residues in target proteins. This often forms multimeric polyubiquitin chains, which is thought to target the protein for destruction.

DRONC

A Drosophila caspase that is degraded in an IAP-dependent manner.

IBM

(IAP-binding motif). A conserved tetrapeptide sequence that is found in caspases and in IAP-regulatory proteins (see Fig. 4). Also known as an RHG (Reaper–Hid–Grim) motif.

TRAIL

(TNF-related apoptosis-inducing ligand). A pro-apoptotic member of the tumour-necrosis factor cytokine family.

OMI/HTRA2

A serine protease that binds to XIAP and regulates cell death.

XAF1

(XIAP-associated factor). An XIAP-binding protein that sequesters XIAP in the nucleus and thereby augments cell death.

NRAGE

(Neurotrophin receptor-interacting MAGE homologue). A recently identified protein that interacts with XIAP after growth-factor withdrawal.

TRAFs

(Tumour-necrosis-factor receptor-associated factors). A group of signalling intermediates (six have been identified in mammals so far), the founding members of which (TRAF1 and TRAF2) were identified in a complex with the cellular IAPs c-IAP1 and c-IAP2, and are associated with the intracellular domain of the type-2 tumour-necrosis-factor receptor.

BMP RECEPTOR

(Bone morphogenic protein receptor). Member of a superfamily of cell-surface receptors that includes the TGF (transforming growth factor)-β receptor. On ligand activation, these receptors transduce signals, mainly through the Smad family of transcription factors and co-activators.

TGF-β RECEPTOR

Member of a superfamily of cell-surface receptors that includes the bone morphogenic protein (BMP) receptors, which, after ligand activation, transduce signals mainly through the Smad family of transcription factors and co-activators.

JNK

(c-Jun amino-terminal kinase). A stress-induced protein kinase that is activated by XIAP.

SMADs

A family of signalling molecules and transcription factors that mediate responses from the TGF (transforming growth factor)-β/ BMP (bone morphogenic protein)-receptor superfamily.

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Salvesen, G., Duckett, C. IAP proteins: blocking the road to death's door. Nat Rev Mol Cell Biol 3, 401–410 (2002). https://doi.org/10.1038/nrm830

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