IAP2 (Drosophila melanogaster)

Description [+]

Synonyms: IAP2, APOPTOSIS 2 INHIBITOR, INHIBITOR OF APOPTOSIS 2, DIAP2, DIAP, IAP HOMOLOG A, DIHA, ILP
Species: Metazoa;Bilateria;Ecdysozoa;Arthropoda;Hexapoda; Drosophila melanogaster
Short gene description: NA
Family: BIR-containing protein : IAP
Process: immunity, apoptosis,
Pathways:
Criteria: manually curated
Curator comment:
Human ortholog(s): BIRC7 cIAP1 BIRC2 BIRC8 XIAP BIRC3
WIKI: IAP2-D_melanogaster

References [+]

The Drosophila inhibitor of apoptosis protein DIAP2 functions in innate immunity and is essential to resist gram-negative bacterial infection.
Leulier F, Lhocine N, Lemaitre B, Meier P
The founding member of the inhibitor of apoptosis protein (IAP) family was originally identified as a cell death inhibitor. However, recent evidence suggests that IAPs are multifunctional signaling devices that influence diverse biological processes. To investigate the in vivo function of Drosophila melanogaster IAP2, we have generated diap2 null alleles. diap2 mutant animals develop normally and are fully viable, suggesting that diap2 is dispensable for proper development. However, these animals were acutely sensitive to infection by gram-negative bacteria. In Drosophila, infection by gram-negative bacteria triggers the innate immune response by activating the immune deficiency (imd) signaling cascade, a NF-kappaB-dependent pathway that shares striking similarities with the pathway of mammalian tumor necrosis factor receptor 1 (TNFR1). diap2 mutant flies failed to activate NF-kappaB-mediated expression of antibacterial peptide genes and, consequently, rapidly succumbed to bacterial infection. Our genetic epistasis analysis places diap2 downstream of or in parallel to imd, Dredd, Tak1, and Relish. Therefore, DIAP2 functions in the host immune response to gram-negative bacteria. In contrast, we find that the Drosophila TNFR-associated factor (Traf) family member Traf2 is dispensable in resistance to gram-negative bacterial infection. Taken together, our genetic data identify DIAP2 as an essential component of the Imd signaling cascade, protecting the organism from infiltrating microbes. Mol Cell Biol. 2006 Nov;26(21):7821-31. Epub 2006 Aug 7.

DIAP2 functions as a mechanism-based regulator of drICE that contributes to the caspase activity threshold in living cells.
Ribeiro PS, Kuranaga E, Tenev T, Leulier F, Miura M, Meier P
In addition to their well-known function in apoptosis, caspases are also important in several nonapoptotic processes. How caspase activity is restrained and shut down under such nonapoptotic conditions remains unknown. Here, we show that Drosophila melanogaster inhibitor of apoptosis protein 2 (DIAP2) controls the level of caspase activity in living cells. Animals that lack DIAP2 have higher levels of drICE activity. Although diap2-deficient cells remain viable, they are sensitized to apoptosis following treatment with sublethal doses of x-ray irradiation. We find that DIAP2 regulates the effector caspase drICE through a mechanism that resembles the one of the caspase inhibitor p35. As for p35, cleavage of DIAP2 is required for caspase inhibition. Our data suggest that DIAP2 forms a covalent adduct with the catalytic machinery of drICE. In addition, DIAP2 also requires a functional RING finger domain to block cell death and target drICE for ubiquitylation. Because DIAP2 efficiently interacts with drICE, our data suggest that DIAP2 controls drICE in its apoptotic and nonapoptotic roles. J Cell Biol. 2007 Dec 31;179(7):1467-80.

References from Human ortholog(s):

The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases.
Eckelman BP, Salvesen GS
cIAPs (cellular inhibitor of apoptosis proteins) 1 and 2 are able to regulate apoptosis when ectopically expressed in recipient cells and probably also in vivo. Previous work suggested that this is at least partially due to direct caspase inhibition, mediated by two of the three baculovirus IAP repeat (BIR) domains that are contained in these proteins. In support of this we show that the BIR domains 2 and 3 of the two cIAPs are able to bind caspases-7 and -9. However, we demonstrate that neither of these BIR domains is able to inhibit caspases because of critical substitutions in the regions that target caspase inhibition in the X-linked IAP, a tight binding caspase inhibitor. The cIAP BIR domains can be converted to tight binding caspase inhibitors by substituting these critical residues with XIAP residues. Thus, cIAPs maintain protein scaffolds suitable for direct caspase inhibition but have lost or never acquired specific caspase inhibitory interaction sites. Consequently, although the binding function of the cIAP BIRs may be important for their physiologic function, caspase inhibition is not. J Biol Chem. 2006 Feb 10;281(6):3254-60. Epub 2005 Dec 8.

X-linked IAP is a direct inhibitor of cell-death proteases.
Deveraux QL, Takahashi R, Salvesen GS, Reed JC
The inhibitor-of-apoptosis (IAP) family of genes has an evolutionarily conserved role in regulating programmed cell death in animals ranging from insects to humans. Ectopic expression of human IAP proteins can suppress cell death induced by a variety of stimuli, but the mechanism of this inhibition was previously unknown. Here we show that human X-chromosome-linked IAP directly inhibits at least two members of the caspase family of cell-death proteases, caspase-3 and caspase-7. As the caspases are highly conserved throughout the animal kingdom and are the principal effectors of apoptosis, our findings suggest how IAPs might inhibit cell death, providing evidence for a mechanism of action for these mammalian cell-death suppressors. Nature. 1997 Jul 17;388(6639):300-4.

The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases.
Eckelman BP, Salvesen GS
cIAPs (cellular inhibitor of apoptosis proteins) 1 and 2 are able to regulate apoptosis when ectopically expressed in recipient cells and probably also in vivo. Previous work suggested that this is at least partially due to direct caspase inhibition, mediated by two of the three baculovirus IAP repeat (BIR) domains that are contained in these proteins. In support of this we show that the BIR domains 2 and 3 of the two cIAPs are able to bind caspases-7 and -9. However, we demonstrate that neither of these BIR domains is able to inhibit caspases because of critical substitutions in the regions that target caspase inhibition in the X-linked IAP, a tight binding caspase inhibitor. The cIAP BIR domains can be converted to tight binding caspase inhibitors by substituting these critical residues with XIAP residues. Thus, cIAPs maintain protein scaffolds suitable for direct caspase inhibition but have lost or never acquired specific caspase inhibitory interaction sites. Consequently, although the binding function of the cIAP BIRs may be important for their physiologic function, caspase inhibition is not. J Biol Chem. 2006 Feb 10;281(6):3254-60. Epub 2005 Dec 8.

IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.
Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, Brink R, Leverkus M, Tergaonkar V, Schneider P, Callus BA, Koentgen F, Vaux DL, Silke J
XIAP prevents apoptosis by binding to and inhibiting caspases, and this inhibition can be relieved by IAP antagonists, such as Smac/DIABLO. IAP antagonist compounds (IACs) have therefore been designed to inhibit XIAP to kill tumor cells. Because XIAP inhibits postmitochondrial caspases, caspase 8 inhibitors should not block killing by IACs. Instead, we show that apoptosis caused by an IAC is blocked by the caspase 8 inhibitor crmA and that IAP antagonists activate NF-kappaB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-kappaB-stimulated production of TNFalpha that killed cells in an autocrine fashion. Inhibition of NF-kappaB reduced TNFalpha production, and blocking NF-kappaB activation or TNFalpha allowed tumor cells to survive IAC-induced apoptosis. Cells treated with an IAC, or those in which cIAP1 was deleted, became sensitive to apoptosis induced by exogenous TNFalpha, suggesting novel uses of these compounds in treating cancer. Cell. 2007 Nov 16;131(4):682-93.

IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis.
Varfolomeev E,Blankenship JW,Wayson SM,Fedorova AV,Kayagaki N,Garg P,Zobel K,Dynek JN,Elliott LO,Wallweber HJ,Flygare JA,Fairbrother WJ,Deshayes K,Dixit VM,Vucic D
Inhibitor of apoptosis (IAP) proteins are antiapoptotic regulators that block cell death in response to diverse stimuli. They are expressed at elevated levels in human malignancies and are attractive targets for the development of novel cancer therapeutics. Herein, we demonstrate that small-molecule IAP antagonists bind to select baculovirus IAP repeat (BIR) domains resulting in dramatic induction of auto-ubiquitination activity and rapid proteasomal degradation of c-IAPs. The IAP antagonists also induce cell death that is dependent on TNF signaling and de novo protein biosynthesis. Additionally, the c-IAP proteins were found to function as regulators of NF-kappaB signaling. Through their ubiquitin E3 ligase activities c-IAP1 and c-IAP2 promote proteasomal degradation of NIK, the central ser/thr kinase in the noncanonical NF-kappaB pathway. Cell. 2007 Nov 16;131(4):669-81.

An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer.
Zender L,Xue W,Zuber J,Semighini CP,Krasnitz A,Ma B,Zender P,Kubicka S,Luk JM,Schirmacher P,McCombie WR,Wigler M,Hicks J,Hannon GJ,Powers S,Lowe SW
Cancers are highly heterogeneous and contain many passenger and driver mutations. To functionally identify tumor suppressor genes relevant to human cancer, we compiled pools of short hairpin RNAs (shRNAs) targeting the mouse orthologs of genes recurrently deleted in a series of human hepatocellular carcinomas and tested their ability to promote tumorigenesis in a mosaic mouse model. In contrast to randomly selected shRNA pools, many deletion-specific pools accelerated hepatocarcinogenesis in mice. Through further analysis, we identified and validated 13 tumor suppressor genes, 12 of which had not been linked to cancer before. One gene, XPO4, encodes a nuclear export protein whose substrate, EIF5A2, is amplified in human tumors, is required for proliferation of XPO4-deficient tumor cells, and promotes hepatocellular carcinoma in mice. Our results establish the feasibility of in vivo RNAi screens and illustrate how combining cancer genomics, RNA interference, and mosaic mouse models can facilitate the functional annotation of the cancer genome. Cell. 2008 Nov 28;135(5):852-64. Epub 2008 Nov 13.

Structure & Sequence [+]

Pfam domains: (Pfam is a large collection of protein families.)

Source	Domain Name	Start	End
PFAM A	BIR	12	77
PFAM A	BIR	116	180
PFAM A	BIR	215	280

Protein sequence [+]

Structure links:

Smartdomain prediction information: SM00238
Smartdomain prediction information: SM00184
Prosite motif and domain information: PS01282
Interpro domain information: Q24307
PFAM domain and domain family information: Q24307

Evolution [+]

Name	Relationship	Species
A_aegypti_AAEL006633-PA	orthology	Aedes
IAP2	orthology	Anopheles
NP_989919.1	orthology	Chicken
BIRC7	orthology	Chicken
IPI00603248.2	orthology	Chicken
BIR_CHICK	orthology	Chicken
BIR_CHICK	orthology	Chicken
NP_989919.1	orthology	Chicken
BIRC3	orthology	Chimpanzee
BIRC3	orthology	Chimpanzee
BIRC2	orthology	Chimpanzee
BIRC2	orthology	Chimpanzee
BIRC8_PANTR	orthology	Chimpanzee
XR_021305.1	orthology	Chimpanzee
XR_021305.1	orthology	Chimpanzee
XIAP	orthology	Chimpanzee
XIAP	orthology	Chimpanzee
NP_001030370.1	orthology	Cow
NP_001030370.1	orthology	Cow
IPI00824732.2	orthology	Cow
Q8WMY4_BOVIN	orthology	Cow
Q8WMY4_BOVIN	orthology	Cow
BIRC7	orthology	Dog
BIRC7	orthology	Dog
Q38JA8_CANFA	orthology	Dog
Q38JA8_CANFA	orthology	Dog
BIRC3_CANFA	orthology	Dog
BIRC3_CANFA	orthology	Dog
Q38IV1_CANFA	orthology	Dog
Q38IV1_CANFA	orthology	Dog
BIRC8	orthology	Fugu
XIAP	orthology	Fugu
BIRC7	orthology	Fugu
BIRC7	orthology	Fugu
BIRC3	orthology	Fugu
BIRC3	orthology	Fugu
BIRC7	orthology	Gasterosteus
BIRC7	orthology	Gasterosteus
BIRC8	orthology	Gasterosteus
XIAP	orthology	Gasterosteus
BIRC3	orthology	Gasterosteus
BIRC3	orthology	Gasterosteus
BIRC3	orthology	Gorilla
BIRC8	orthology	Gorilla
BIRC2	orthology	Gorilla
BIRC2	orthology	Gorilla
BIRC7	orthology	Gorilla
BIRC7	orthology	Gorilla
XIAP	orthology	Gorilla
XIAP	orthology	Gorilla
BIRC2	orthology	Horse
BIRC2	orthology	Horse
BIRC3	orthology	Horse
BIRC3	orthology	Horse
BIRC8	orthology	Horse
XIAP	orthology	Horse
BIRC7	orthology	Horse
BIRC7	orthology	Horse
BIRC7	orthology	Human
BIRC7	orthology	Human
cIAP1	orthology	Human
BIRC2	orthology	Human
BIRC8	orthology	Human
BIRC8	orthology	Human
XIAP	orthology	Human
XIAP	orthology	Human
BIRC3	orthology	Human
BIRC3	orthology	Human
BIRC7	orthology	Lyzard
BIRC7	orthology	Lyzard
A_carolinensis_ENSACAP00000011315	orthology	Lyzard
A_carolinensis_ENSACAP00000011315	orthology	Lyzard
A_carolinensis_ENSACAP00000012475	orthology	Lyzard
A_carolinensis_ENSACAP00000012475	orthology	Lyzard
BIRC2	orthology	Macaca
BIRC7	orthology	Macaca
BIRC7	orthology	Macaca
BIRC3	orthology	Macaca
BIRC3	orthology	Macaca
BIRC2	orthology	Macaca
BIRC8	orthology	Medaka
XIAP	orthology	Medaka
BIRC7	orthology	Medaka
BIRC7	orthology	Medaka
BIRC3	orthology	Medaka
M_domestica_ENSMODP00000000705	orthology	Monodelphis
M_domestica_ENSMODP00000000705	orthology	Monodelphis
M_domestica_ENSMODP00000000728	orthology	Monodelphis
XM_001362587.1	orthology	Monodelphis
M_domestica_ENSMODP00000018715	orthology	Monodelphis
XM_001364568.1	orthology	Monodelphis
BIRC7	orthology	Monodelphis
BIRC7	orthology	Monodelphis
cIAP2	orthology	Mouse
Birc3	orthology	Mouse
cIAP1	orthology	Mouse
Birc2	orthology	Mouse
Birc7	orthology	Mouse
Birc7	orthology	Mouse
Xiap	orthology	Mouse
Xiap	orthology	Mouse
BIRC3	orthology	Orangutan
BIRC3	orthology	Orangutan
Q5R9T1_PONPY	orthology	Orangutan
Q5R9T1_PONPY	orthology	Orangutan
BIRC7	orthology	Orangutan
BIRC7	orthology	Orangutan
XIAP	orthology	Orangutan
XIAP	orthology	Orangutan
O_anatinus_ENSOANP00000006435	orthology	Ornithorhynchus
O_anatinus_ENSOANP00000006435	orthology	Ornithorhynchus
O_anatinus_ENSOANP00000016616	orthology	Ornithorhynchus
O_anatinus_ENSOANP00000016616	orthology	Ornithorhynchus
BIRC7	orthology	Rabbit
O_cuniculus_ENSOCUP00000008505	orthology	Rabbit
XIAP	orthology	Rabbit
BIRC3	orthology	Rabbit
BIRC3	orthology	Rabbit
O_cuniculus_ENSOCUP00000011948	orthology	Rabbit
O_cuniculus_ENSOCUP00000011948	orthology	Rabbit
O_cuniculus_ENSOCUP00000014265	orthology	Rabbit
Birc3	orthology	Rat
NP_076477.2	orthology	Rat
Birc4	orthology	Rat
XIAP_RAT	orthology	Rat
Birc2	orthology	Rat
NP_068520.2	orthology	Rat
BIRC7	orthology	Tetraodon
BIRC7	orthology	Tetraodon
BIRC3	orthology	Tetraodon
BIRC8	orthology	Tetraodon
XIAP	orthology	Tetraodon
BIRC7	orthology	Xenopus
BIRC7	orthology	Xenopus
X_tropicalis_ENSXETP00000030727	orthology	Xenopus
X_tropicalis_ENSXETP00000030727	orthology	Xenopus
birc4	orthology	Xenopus
birc4	orthology	Xenopus
birc3	orthology	Xenopus
birc3	orthology	Xenopus
T_guttata_ENSTGUP00000003825	orthology	Zebra finch
XIAP	orthology	Zebra finch
BIRC7	orthology	Zebra finch
BIRC7	orthology	Zebra finch
T_guttata_ENSTGUP00000013125	orthology	Zebra finch
BIRC2	orthology	Zebra finch
birc4	orthology	Zebrafish
xiap	orthology	Zebrafish
birc2	orthology	Zebrafish
birc2	orthology	Zebrafish
BIRC7	orthology	Zebrafish
zgc:165605	orthology	Zebrafish
Q5MM83_AEDAE	paralogy	Aedes
IAP4	paralogy	Anopheles
IAP3	paralogy	Anopheles
A_gambiae_AGAP007293-PA	paralogy	Anopheles
IAP1	paralogy	Anopheles
IAP4	paralogy	Anopheles
P_troglodytes_ENSPTRP00000048273	paralogy	Chimpanzee
XM_001156604.1	paralogy	Chimpanzee
C_intestinalis_ENSCINP00000011648	paralogy	Ciona
C_intestinalis_ENSCINP00000020067	paralogy	Ciona
NA	paralogy	Ciona
C_intestinalis_ENSCINP00000021651	paralogy	Ciona
C_intestinalis_ENSCINP00000000045	paralogy	Ciona
C_intestinalis_ENSCINP00000000047	paralogy	Ciona
C_intestinalis_ENSCINP00000000466	paralogy	Ciona
NA	paralogy	Ciona
C_intestinalis_ENSCINP00000000487	paralogy	Ciona
C_intestinalis_ENSCINP00000000510	paralogy	Ciona
C_intestinalis_ENSCINP00000002256	paralogy	Ciona
C_intestinalis_ENSCINP00000002312	paralogy	Ciona
C_intestinalis_ENSCINP00000005161	paralogy	Ciona
C_intestinalis_ENSCINP00000009820	paralogy	Ciona
C_intestinalis_ENSCINP00000010449	paralogy	Ciona
IPI00689691.3	paralogy	Cow
IPI00689691.3	paralogy	Cow
th	paralogy	Fly
E_caballus_ENSECAP00000002314	paralogy	Horse
XP_001504091.2	paralogy	Horse
BIRC1	paralogy	Human
NAIP	paralogy	Human
A_carolinensis_ENSACAP00000009897	paralogy	Lyzard
A_carolinensis_ENSACAP00000009897	paralogy	Lyzard
Naip1	paralogy	Mouse
Naip4	paralogy	Mouse
Naip5	paralogy	Mouse
Naip5	paralogy	Mouse
Birc1-rs1	paralogy	Mouse
Naip6	paralogy	Mouse
Naip2	paralogy	Mouse
Naip2	paralogy	Mouse
P_pygmaeus_ENSPPYP00000017359	paralogy	Orangutan
P_pygmaeus_ENSPPYP00000017359	paralogy	Orangutan
Q8R4U8_RAT	paralogy	Rat
RGD1559914_predicted	paralogy	Rat
X_tropicalis_ENSXETP00000016312	paralogy	Xenopus
X_tropicalis_ENSXETP00000016315	paralogy	Xenopus
X_tropicalis_ENSXETP00000034890	paralogy	Xenopus
X_tropicalis_ENSXETP00000057704	paralogy	Xenopus

Gene Ontology [+]

GO id	Name	Ontology type	Evidence
GO:0008152	metabolic process	biological_proccess	IEA
GO:0016998	cell wall catabolic process	biological_proccess	IEA
GO:0019835	cytolysis	biological_proccess	IEA
GO:0042742	defense response to bacterium	biological_proccess	IEA
GO:0003796	lysozyme activity	mollecular_function	IEA
GO:0003824	catalytic activity	mollecular_function	IEA
GO:0004568	chitinase activity	mollecular_function	IDA
GO:0016787	hydrolase activity	mollecular_function	IEA
GO:0016798	hydrolase activity, acting on glycosyl bonds	mollecular_function	IEA
GO:0005576	extracellular region	cell_component	IEA

Check GO Evidence Codes here

Information from other databases [+]

Gene related links:

Gene info from FyBase [?] FBgn0015247
Ensembl genome browser [?] : FBgn0015247
Expression info from Arrayexpress [?] : FBgn0015247
Protein expression from Protein Atlas: [?] FBgn0015247

Protein related links:

Uniprot protein info: Q24307
PIR protein info: Q24307
Protein interactions from IntAct: Q24307

Other links

entrezgene: 36748
refseq_dna: NM_176182
refseq_dna: NM_057779
refseq_peptide: NP_477127
refseq_peptide: NP_788362

Click on [?] for more information.