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First published online October 22, 2008
doi: 10.1242/10.1242/jcs.040303

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Diverse functions within the IAP family

¹ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
² Department of Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
³ Department of Graduate Program in Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA

^* Author for correspondence (e-mail: colind{at}umich.edu)

	Introduction

Top Introduction Smac mimetics and IAP... Other functions of IAPs Conclusion References

 
Inhibitors of apoptosis (IAPs) are a diverse group of signaling molecules that function in a wide range of cellular roles, from the inhibition of caspases to the promotion of cell-cycle progression. These diverse functions may well be linked to the many different domains that are contained within different proteins in the family. IAP family members were first described as inhibitors of apoptosis in baculoviruses, and are therefore identified by the presence of baculovirus IAP repeat (BIR) domains. However, it is becoming increasingly evident that, although the family-defining BIR domain is highly conserved, distinct BIR domains, even within the same protein, have different functions (Eckelman et al., 2006; Srinivasula and Ashwell, 2008). Additionally, RING domains, which have been described in many proteins to have E3 ubiquitin ligase function, are present in several IAP family members. Two IAPs, c-IAP1 (also known as BIRC2) and c-IAP2 (also known as BIRC3), each contain a caspase-recruitment domain (CARD), which is thought to mediate protein-protein interactions. Furthermore, some unique protein domains are found within the IAP family, including a nucleotide-binding and oligomerization domain (NOD) and a leucine-rich repeat (LRR) in neuronal apoptosis inhibitory protein (NAIP; also known as BIRC1) (Fritz et al., 2006), and a ubiquitin-conjugating (UBC) domain in Apollon (also known as BIRC6) (Bartke et al., 2004).

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	Smac mimetics and IAP signaling

Top Introduction Smac mimetics and IAP... Other functions of IAPs Conclusion References

 
XIAP is thought to be the only member of the human IAP family that can directly bind and inhibit the caspases that carry out the cell-death program (Eckelman et al., 2006; Srinivasula and Ashwell, 2008). XIAP binds to caspase-9 through the most C-terminal BIR domain (BIR3), whereas caspase-3 and caspase-7 bind through BIR2, the middle of the three BIRs. Recent data indicate that the C-terminal RING domain is required for the anti-apoptotic activity of XIAP; however, this might be directly related to reduced protein stability (Schile et al., 2008). Binding of XIAP to caspases is antagonized by several mitochondrial proteins, most notably second mitochondrial activator of caspases (Smac), which is released following the loss of mitochondrial integrity during apoptosis (Vaux and Silke, 2003). The potential of this XIAP-Smac interaction to sensitize cells to apoptosis led to the pursuit of molecules that would mimic Smac, and therefore inhibit XIAP, as anti-cancer therapies (Holcik et al., 2001; Wright and Duckett, 2005). Several small molecules have been developed that can induce death in tumor cells, either alone or in combination with established chemotherapeutics. For example, certain tumor-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-resistant tumor cells can be sensitized to TRAIL-induced death when used in combination with a Smac mimetic drug (Li et al., 2004).

Previous studies have shown that c-IAP1 binds via its BIR1 domain to a key intracellular signaling intermediate, TNF-receptor-associated factor 2 (TRAF2), which is known to be essential for several signaling pathways. These two proteins transduce signals from TNF-receptor family members, becoming part of the signaling complex of the TNF receptors. Additionally, c-IAP1 can bind caspases but is not thought to inhibit apoptotic cell death through this binding (Eckelman et al., 2006; Tenev et al., 2004). Interestingly, both proteins are degraded rapidly upon treatment with Smac mimetics, which confers a pro-apoptotic phenotype. This mechanism of cell death, which is induced by c-IAP1 degradation, appears to be dependent on TNF (Srinivasula and Ashwell, 2008; Wu et al., 2007; Varfolomeev and Vucic, 2008).

Smac mimetics have helped to elucidate functions of c-IAP1, showing that, under normal conditions, c-IAP1 acts as an E3 ubiquitin ligase (probably through its RING domain) for nuclear factor-B (NF-B)-inducing kinase (NIK), maintaining low basal levels of NIK and preventing NF-B signaling (Srinivasula and Ashwell, 2008; Wu et al., 2007; Varfolomeev and Vucic, 2008). The loss of c-IAP1 (through degradation by Smac or Smac mimetics, for example) results in phosphorylation and activation of downstream signaling molecules, including NIK, ultimately leading to the translocation of NF-B dimers into the nucleus to activate NF-B-dependent transcription. NF-B activation induces the expression of TNF, which can exert an autocrine effect on the cell. In the absence of c-IAP1, TNF-receptor ligation results in the deubiquitylation of the receptor-associated kinase RIP1 (receptor-interacting protein 1) by the tumor-suppressor protein CYLD (cylindromatosis) and in the induction of a death-inducing complex – which includes RIP1, FADD (Fas-associated death-domain protein) and activated caspase-8 – culminating in cell death through caspase-3 activation (Wang et al., 2008). Smac mimetics have thus greatly enhanced our understanding both of the signaling functions of c-IAP1 and the consequences of TNF-receptor signaling.

	Other functions of IAPs

Top Introduction Smac mimetics and IAP... Other functions of IAPs Conclusion References

 
XIAP has also been implicated in other cellular processes besides the suppression of apoptosis, including the control of NF-B-dependent transcription. TNF-receptor ligation activates the canonical NF-B pathway by phosphorylating the inhibitor of B (IB) kinase (IKK) complex, which results in phosphorylation and degradation of IB and release of NF-B dimers into the nucleus. The phosphorylation of the IKK complexes is performed by transforming growth factor-β (TGFβ)-activated kinase 1 (TAK1) (Hayden and Ghosh, 2008), a mitogen-activated protein kinase kinase kinase (MAP3K) that is also involved in Jun N-terminal kinase (JNK) signaling. XIAP has been shown to bind TAK1-binding protein 1 (TAB1) through the most N-terminal BIR domain (BIR1), which in turn activates TAK1. Activation of TAK1 results in both NF-B and JNK activation, and is thought to enhance the anti-apoptotic function of XIAP (Lu et al., 2007). XIAP BIR1, although homologous to BIR2 and BIR3, does not have caspase-inhibitory activity, and this role in the activation of TAK1 illustrates the diversity of functions within the IAP family.

XIAP has also been shown to interact with Cu²⁺ metabolism (Murr1) domain-containing 1 (COMMD1), a Cu²⁺-metabolism protein, and through this interaction has effects on two different signaling pathways (Maine and Burstein, 2007; Mufti et al., 2007). The importance of COMMD1 in Cu²⁺ export from the cell is evidenced by loss of COMMD1, which results in a Cu²⁺ toxicosis syndrome, which is common in Bedlington terriers. XIAP binds COMMD1 through its BIR3 domain and catalyzes COMMD1 ubiquitylation through the RING domain. This downregulation of COMMD1 by XIAP can thus increase intracellular Cu²⁺ levels. Homeostasis of Cu²⁺ metabolism is achieved through a negative-feedback loop, in which higher Cu²⁺ levels have a negative effect on XIAP, causing its inhibition and ultimate degradation. The second pathway of XIAP function through COMMD1 regulation is related to the role of COMMD1 as an inhibitor of NF-B. COMMD1 has been shown to bind and catalyze the ubiquitylation of DNA-bound RelA, a key NF-B subunit, thus suppressing NF-B-dependent transcription. Because XIAP can in turn catalyze the ubiquitylation of COMMD1, it can prevent this inhibition and allow NF-B-dependent transcription to continue (Maine and Burstein, 2007; Mufti et al., 2007). The physiological consequences of the XIAP-COMMD1 interaction remain to be elucidated.

The functions of two members of the IAP family, NAIP and Apollon, are not yet fully understood. Both of these proteins contain domains that are unique to the IAP family. NAIP was the first mammalian member of the IAP family to be identified, and it was found in connection with spinal muscular atrophy, being contained within the locus responsible for the disease (Roy et al., 1995). In studies using mice that are deficient in NAIP5, one of the several paralogs of NAIP, this protein was shown to contribute to the sensing of bacterial flagellin and subsequent activation of caspase-1 for pyroptotic cell death (Carneiro et al., 2007; Delbridge and O'Riordan, 2007; Lightfield et al., 2008). This has been supported by work with the human protein (Vinzing et al., 2008) and represents perhaps the best-understood function of NAIP, because its anti-apoptotic properties remain unclear. The function of Apollon, the largest member of the mammalian IAP family (Chen et al., 1999), is even more controversial. Interestingly, a deficiency in Apollon in mice leads to embryonic lethality owing to excessive apoptosis of the placenta, which is a far more striking phenotype than that caused by loss of the better-characterized XIAP. It appears that the anti-apoptotic function of Apollon resides in the C-terminal UBC domain, rather than the single BIR domain (Ren et al., 2005). Apollon has also recently been described to participate as a coordinator of multiple processes during cytokinesis (Pohl and Jentsch, 2008), which again illustrates the diversity of functions within the IAP family.

Survivin (also known as BIRC5) is the smallest member of the mammalian IAP family, containing only one BIR domain and no other functional domains (Sah et al., 2006; Altieri, 2003). Its simplicity belies its apparent importance in two separate processes that are crucial for cell homeostasis: cell-cycle regulation and inhibition of apoptosis. Interestingly, survivin has been reported to be upregulated in cancer cells, although it is possible that this upregulation is simply indicative of cancer cells cycling at a greater rate than the rest of the cell population, because survivin is regulated in a cell-cycle-dependent manner (Sah et al., 2006; Altieri, 2003). Evidence for the role of survivin in cell-cycle regulation is indicated by loss of the protein resulting in arrest or mitotic catastrophe in cycling cells. Survivin binds to the AuroraB kinase and the inner centromere protein (INCENP) during cytokinesis, and might have other functions in promoting cell division. Additionally, studies have suggested that survivin can inhibit cell death, possibly through the binding of Smac to its single BIR, removing the ability of Smac to inhibit XIAP (Sah et al., 2006; Altieri, 2003).

	Conclusion

Top Introduction Smac mimetics and IAP... Other functions of IAPs Conclusion References

 
Our understanding of the IAP family has clearly moved far beyond the originally described function as caspase inhibitors. It is increasingly apparent that the family-defining BIR domain has evolved for signaling in concert with Smac, because the ability of IAPs to bind Smac is more widely retained than is caspase inhibition. The interaction of BIRs with Smac has been shown to result in a variety of cellular outcomes, which have remarkable consequences in the context of cancer therapeutics. The other domains that are present in IAP family members, such as the RING domain, also clearly diversify the functions of these proteins to have effects in other cellular processes. Future studies will further clarify how each of these functions of IAPs participate in the maintenance of cellular homeostasis.

	References

Top Introduction Smac mimetics and IAP... Other functions of IAPs Conclusion References

 

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This Article Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rumble, J. M. Articles by Duckett, C. S. Search for Related Content PubMed PubMed Citation Articles by Rumble, J. M. Articles by Duckett, C. S. Social Bookmarking                         What's this?