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FLASH GENE

Symbol

XIAP

contributors: shn/mct - updated : 19-10-2019

HGNC name	X-linked inhibitor of apoptosis
HGNC id	592

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive esophagus       highly   intestine large intestine colon     Endocrine pancreas       highly Lymphoid/Immune lymph node       highly   spleen         Reproductive male system prostate       Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic leukocyte Blood/Hematopoietic neutrophil

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	three baculovirus IAP repeat (BIR1-2 domains required for inhibition of caspase 3/7)
	the BIR1 domain directly interacts with MA1P3K7IP1 to induce NF-kappaB activation
	a C-terminal RING zinc finger domain (BIR3 Ring inhibitor of caspase 9), mediating MAP3K7 polyubiquitination, which then targets this molecule for proteosomal degradation, and is essential for NOD2 signaling
	BIR and RING finger domains of XIAP contain multiple cysteine residues and are potential targets for S-nitrosylation

conjugated

ubiquitinated

mono polymer

homomer , monomer , dimer

HOMOLOGY

interspecies	ortholog to Xiap, Mus musculus
	ortholog to Xiap, Rattus norvegicus
	ortholog to xiap, Danio rerio
	ortholog to XIAP, Pan troglodytes

intraspecies

homolog to NAIP

Homologene

FAMILY

IAP family

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus
text	VGLL4 triggers a relocalization of XIAP from the cytoplasm to the nucleus

basic FUNCTION	a direct inhibitor of cell-death proteases
	inhibitor of apoptosis through binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2
	antiapoptosis activity in a variety of apoptosis inducing conditions
	has a ubiquitin protein ligase activity in response to apoptotic stimuli
	involved in the protection of the neonatal brain against hypoxia-ischemia
	potent suppressor of apoptosis that directly inhibits specific members of the caspase family (caspase 3, 7, 9) of cysteine proteases, playing a role in the control of intracellular copper levels
	playing an essential role in the cell death mechanism of injured motoneurons in collaboration with BIRC4BP, BIRC3, BIRC2
	required for the survival and/or differentiation of NKT cells, and potent regulator of lymphocyte homeostasis
	functioning as ubiquitin ligase toward mature CASP9 and DIABLO to inhibit apoptosis
	inhibits c-Jun N-terminal kinase 1 (MAPK8) activation by transforming growth factor beta1 (TGF-beta1) through ubiquitin-mediated proteosomal degradation of the TGF-beta1-activated kinase 1 (MAP3K7)
	can function as a cofactor in the regulation of gene expression by transforming growth factor-beta (TGF-beta)
	having a role in control of oxidative stress and mitochondrial antioxidants that may contribute to cell protection after various injuries
	mediating activation of MAP3K7/TAK1, leading to the activation of NF Kappa B
	is essential for the shear stress-stimulated SRC/PTK2/ERK signaling pathway
	is a nonredundant modulator of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)
	has a role in copper metabolism
	critical controller of apoptotic susceptibility of effector T cell function
	plays a novel role in endothelial cells and acting as a regulator of vascular antiatherogenic function
	promoting the binding of STUB1 to the RAF1/Hsp90 complex
	acting as an E3 ubiquitin ligase for PTEN, promoting Akt activity by regulating PTEN content and compartimentalization
	critical discriminator between type I and type II apoptosiscritical discriminator between type I and type II apoptosis signalling
	playing a role in regulating innate immune responses by interacting with NOD1 and NOD2 through interaction with RIPK2
	protects gangkion cells after axotonomy of the optic nerve, increased intraocular pressure and retinal ischemia ,
	confers structural neuroprotection of photoreceptors after retinal detachment
	recruits focal adhesion kinase (PTK2) into integrin-associated focal adhesions, controlling cell migration
	plays a key role in shear stress-stimulated ERK activation by maintaining the Src-accessible location of PTK2
	important mediator for the recruitment of PTK2 into the focal adhesion site
	may play a preventative role in cardiovascular disease
	its inhibition are essential to limit clonogenicity of Type I tumor cells after TNFSF10 receptor stimulation )
	negatively regulate GDI1 SUMOylation, which might affect its activity in controlling cell motility
	has the function of regulating cell motility via regulation of beta-actin polymerization and cytoskeleton formation
	XIAP, BIRC2, BIRC3 are important regulators of inflammatory processes in endothelial cells
	plays a key role in vascular functions of PTK2B or PTK2B domain-mediated vascular functions of PTK2
	is essential for functional activity of PTK2B in endothelial cells
	regulates a diversity of vascular functions linked to PTK2 and(or) PTK2B
	potent regulator of innate immune responses
	co-ordinated development of the brain and face is likely dependent in part upon XIAP mediation of HH/PTCH1-regulated cell survival and apoptosis during embryogenesis
	XIAP and BIRC2 induce autophagy by upregulating the transcription of BECN1, an essential autophagy gene
	regulate innate immune signaling
	plays a key role in the control of mitotic cell death
	XIAP ubiquitinates a highly conserved Lys residue in AC isoforms and thereby accelerates the endocytosis and degradation of multiple AC isoforms in human cell lines

CELLULAR PROCESS	cell life, cell death/apoptosis
	cell life, antiapoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	HNRPC 1/2 IRES form are part of a complex modulating BIRC4 expression
	complexing with BIRC4BP to regulate motoneuron resistance to apoptotic cell death
	XIAP-CCS complex implicated in apoptosis, copper metabolism, and redox regulation

INTERACTION

DNA

RNA

small molecule

protein	DIABLO (direct IAP binding protein with low pI)
	TRAF1 and TRAF2
	COMMD1, a factor recently implicated in copper homeostasis (functioning through COMMD1 to regulate copper homeostasis)
	MAP3K7IP1 and AIFM1
	acting cooperatively with BIRC3 and BIRC2 via nonredundant pathways to regulate genotoxic stress-induced nuclear factor-kappaB activation
	KCNJ6/MAP3K7IP1 interaction is crucial for BIRK4-induced MAP3K7 and NF-kappaB activation
	RIPK2 via its BIR2 domain, which could be disrupted by XIAP antagonists SMAC and SMAC-mimicking compounds
	inhibitor of caspase-3, -7 and -9
	mediates activation of MAP3K7/TAK1, leading to the activation of NF-kappa-B
	GSPT1/eRF3 protein
	HtrA2, mammalian homologue of the Escherichia coli heat shock-inducible protein HtrA
	neurotrophin receptor-interacting MAGE homologue (NRAGE)
	ILPIP (hILP-Interacting Protein)
	TAB1-TAK1 receptors
	XIAP-associated factor 1 (XAF1)
	survivin (BIRC5)
	checkpoint kinase Chk1
	enhances NF-kappaB activity
	interacts with and ubiquitinates MEKK2
	binds strongly to C-RAF and promotes the ubiquitylation of C-RAF in vivo through the Hsp90-mediated quality control system
	interacting with AIFM1 (role for XIAP in regulating cellular reactive oxygen species)
	caveolin-1 (CAV1)
	role for XIAP in regulating innate immune responses by interacting with NOD1 and NOD2 through interaction with RIPK2
	interacting with HAX1, that enhances the stability of XIAP against proteosomal degradation and thus contributing to inhibition of apoptosis
	regulates actin polymerization and cell motility through its interaction with GDI1
	VGLL4 triggers a relocalization of XIAP from the cytoplasm to the nucleus
	interacts with PTK2B, suggesting cross-talk between XIAP and PTK2B
	interacted with ARHGDIA via its RING domain and negatively modulated ARHGDIA SUMOylation
	XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly complex (LUBAC) to NOD2
	platelets have a functional intrinsic apoptotic-signalling pathway including the pro-apoptotic protease HTRA2 and its target protein XIAP
	XIAP and, to a lesser extent, BIRC2 were found to directly interact with RHOA independently of the RHOA activation status
	controls RIPK3-dependent cell death and IL1B secretion in response to TNF, which might contribute to hyperinflammation in patients with XLP2
	XIAP directly interacts with MAP3K3 and competes with PB1 domain-mediated binding to MAP2K5
	SERTAD1 may render cancer cells resistant to apoptosis through the stabilization of XIAP
	XIAP is a target for USP11, and stabilization of XIAP due to its deubiquitylation by USP11 leads to the inhibition of cell anoikis and apoptosis, which in turn promotes tumorigenesis
	SERTAD1 acts as an adaptor that bridges the interaction of multiple Adenylyl cyclases (ACs) isoforms with XIAP, a RING-domain E3 ubiquitin ligase
	XIAP serves as an E3 ligase for BCL2 and SEPTIN4 is essential for this process
	SEPTIN4 interacts with X-linked inhibitor of apoptosis (XIAP) in the ntestinal stem cell (ISC) niche to regulate stem cell survival during intestinal homeostasis and regeneration
	CYP1B1 may play an important role in preventing ubiquitin-proteasome-mediated XIAP degradation through the activation of PRKCE signaling in cancer cells

cell & other

REGULATION

activated by

Che-1 in response to DNA damage

inhibited by	SMAC which neutralizes the ability of BIRC4 to repress active caspase 9
	interaction with PRSS25
	AFP

repressed by

S-nitrosylation (does not affect its E3 ligase activity, but instead directly compromising its anticaspase-3 and antiapoptotic function, and contributes to Parkinson disease pathogenesis)

Phosphorylated by

by CDK1-CCNB1 that controls mitotic cell death

Other	degraded by calpain contribution to initiation of apoptosis in neutrophils
	neutrophils accumulation
	ubiquitinated and degraded by the proteasome in apoptotic cells
	phosphorylation by PKB/AKT protects against ubiquitination
	p34SEI-1 protects the X-linked inhibitor of apoptosis protein (XIAP) from degradation
	phosphorylated by yclic AMP-dependent protein kinase A (PKA)
	directly ubiquitinated by TRIM32

ASSOCIATED DISORDERS

corresponding disease(s)

XLP2

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in hepatocellular carcinoma tumoral   deletion     in X-linked lymphoproliferative syndrome, and in patients with low numbers of natural killer T-lymphocytes (NKT cells) constitutional     --low   renders cells highly sensitive to oxidative stress tumoral     --over   in the majority of non-small cell lung carcinoma, together with the abundant or upregulated expression of HBXIP and BIRC5 suggest that tumours are endowed with resistance against a variety of apoptosis-inducing conditions tumoral     --over   overexpression of FOXM1, XIAP, and BIRC5 contributes to the development of drug-resistance and is associated with poor clinical outcome in breast cancer patients

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer digestive liver for gene therapy in hepatocellular carcinoma (inhibition of the NF-kappaB/XIAP signaling pathway might selectively abolish the pro-oncogenic activity of TGF-beta1 in advanced hepatocellular carcinomas without affecting the pro-apoptotic effects of TGF-bet cancer     inhibition as a treatment for malignancy cancer digestive colon targeting CFLAR and BIRC4 may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis cardiovascular     may be target protein for the prevention of cardiovascular disease cancer     potential utilization of XIAP as a target for cancer prevention and therapy cancer endocrine thyroid XIAP inhibitor can be therapeutically targeted, either alone or in combination, to induce efficient apoptosis in PTC with overexpression of XIAP

ANIMAL & CELL MODELS

mice deficient in Xiap gene were viable, histopathological analysis did not reveal any differences between IAP-deficient and wild-type mice and any defects in induction of caspase-dependent or -independent apoptosis in cells was found