TISIDB

Summary
Symbol	XIAP
Name	X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase
Aliases	hILP; API3; BIRC4; baculoviral IAP repeat-containing 4; X-linked inhibitor of apoptosis; IAP-3; ILP1; MIHA; ......
Chromosomal Location	Xq25
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Cytoplasm. Nucleus. Note=TLE3 promotes its nuclear localization.
Domain	PF00653 Inhibitor of Apoptosis domain
Function	Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program.

> Gene Ontology [ TOP ]
Biological Process	GO:0000209 protein polyubiquitination GO:0002218 activation of innate immune response GO:0002221 pattern recognition receptor signaling pathway GO:0002753 cytoplasmic pattern recognition receptor signaling pathway GO:0002757 immune response-activating signal transduction GO:0002758 innate immune response-activating signal transduction GO:0002764 immune response-regulating signaling pathway GO:0007178 transmembrane receptor protein serine/threonine kinase signaling pathway GO:0010466 negative regulation of peptidase activity GO:0010951 negative regulation of endopeptidase activity GO:0010955 negative regulation of protein processing GO:0016055 Wnt signaling pathway GO:0016485 protein processing GO:0030111 regulation of Wnt signaling pathway GO:0030177 positive regulation of Wnt signaling pathway GO:0030509 BMP signaling pathway GO:0030510 regulation of BMP signaling pathway GO:0030522 intracellular receptor signaling pathway GO:0031349 positive regulation of defense response GO:0031396 regulation of protein ubiquitination GO:0031398 positive regulation of protein ubiquitination GO:0035872 nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway GO:0043154 negative regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0043281 regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0045088 regulation of innate immune response GO:0045089 positive regulation of innate immune response GO:0045861 negative regulation of proteolysis GO:0050727 regulation of inflammatory response GO:0051346 negative regulation of hydrolase activity GO:0051604 protein maturation GO:0052547 regulation of peptidase activity GO:0052548 regulation of endopeptidase activity GO:0055070 copper ion homeostasis GO:0055076 transition metal ion homeostasis GO:0060070 canonical Wnt signaling pathway GO:0060828 regulation of canonical Wnt signaling pathway GO:0070423 nucleotide-binding oligomerization domain containing signaling pathway GO:0070424 regulation of nucleotide-binding oligomerization domain containing signaling pathway GO:0070613 regulation of protein processing GO:0071772 response to BMP GO:0071773 cellular response to BMP stimulus GO:0090092 regulation of transmembrane receptor protein serine/threonine kinase signaling pathway GO:0090263 positive regulation of canonical Wnt signaling pathway GO:0090287 regulation of cellular response to growth factor stimulus GO:0097039 protein linear polyubiquitination GO:0097340 inhibition of cysteine-type endopeptidase activity GO:0097341 zymogen inhibition GO:0198738 cell-cell signaling by wnt GO:1902528 regulation of protein linear polyubiquitination GO:1902530 positive regulation of protein linear polyubiquitination GO:1902914 regulation of protein polyubiquitination GO:1902916 positive regulation of protein polyubiquitination GO:1903317 regulation of protein maturation GO:1903318 negative regulation of protein maturation GO:1903320 regulation of protein modification by small protein conjugation or removal GO:1903322 positive regulation of protein modification by small protein conjugation or removal GO:1990001 inhibition of cysteine-type endopeptidase activity involved in apoptotic process GO:2000116 regulation of cysteine-type endopeptidase activity GO:2000117 negative regulation of cysteine-type endopeptidase activity
Molecular Function	GO:0004842 ubiquitin-protein transferase activity GO:0004857 enzyme inhibitor activity GO:0004866 endopeptidase inhibitor activity GO:0004869 cysteine-type endopeptidase inhibitor activity GO:0016874 ligase activity GO:0019787 ubiquitin-like protein transferase activity GO:0030414 peptidase inhibitor activity GO:0043027 cysteine-type endopeptidase inhibitor activity involved in apoptotic process GO:0043028 cysteine-type endopeptidase regulator activity involved in apoptotic process GO:0061134 peptidase regulator activity GO:0061135 endopeptidase regulator activity GO:0061630 ubiquitin protein ligase activity GO:0061659 ubiquitin-like protein ligase activity
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04064 NF-kappa B signaling pathway hsa04120 Ubiquitin mediated proteolysis hsa04210 Apoptosis hsa04510 Focal adhesion hsa04621 NOD-like receptor signaling pathway
Reactome	R-HSA-109581: Apoptosis R-HSA-111471: Apoptotic factor-mediated response R-HSA-3769402: Deactivation of the beta-catenin transactivating complex R-HSA-73887: Death Receptor Signalling R-HSA-109606: Intrinsic Pathway for Apoptosis R-HSA-5357801: Programmed Cell Death R-HSA-5213460: RIPK1-mediated regulated necrosis R-HSA-5218859: Regulated Necrosis R-HSA-5357905: Regulation of TNFR1 signaling R-HSA-5675482: Regulation of necroptotic cell death R-HSA-111463: SMAC binds to IAPs R-HSA-111469: SMAC-mediated apoptotic response R-HSA-111464: SMAC-mediated dissociation of IAP R-HSA-162582: Signal Transduction R-HSA-195721: Signaling by Wnt R-HSA-201681: TCF dependent signaling in response to WNT R-HSA-75893: TNF signaling R-HSA-5357956: TNFR1-induced NFkappaB signaling pathway

> KEGG and Reactome Pathway

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KEGG

hsa04064 NF-kappa B signaling pathway
hsa04120 Ubiquitin mediated proteolysis
hsa04210 Apoptosis
hsa04510 Focal adhesion
hsa04621 NOD-like receptor signaling pathway

Reactome

R-HSA-109581: Apoptosis
R-HSA-111471: Apoptotic factor-mediated response
R-HSA-3769402: Deactivation of the beta-catenin transactivating complex
R-HSA-73887: Death Receptor Signalling
R-HSA-109606: Intrinsic Pathway for Apoptosis
R-HSA-5357801: Programmed Cell Death
R-HSA-5213460: RIPK1-mediated regulated necrosis
R-HSA-5218859: Regulated Necrosis
R-HSA-5357905: Regulation of TNFR1 signaling
R-HSA-5675482: Regulation of necroptotic cell death
R-HSA-111463: SMAC binds to IAPs
R-HSA-111469: SMAC-mediated apoptotic response
R-HSA-111464: SMAC-mediated dissociation of IAP
R-HSA-162582: Signal Transduction
R-HSA-195721: Signaling by Wnt
R-HSA-201681: TCF dependent signaling in response to WNT
R-HSA-75893: TNF signaling
R-HSA-5357956: TNFR1-induced NFkappaB signaling pathway

Summary
Symbol	XIAP
Name	X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase
Aliases	hILP; API3; BIRC4; baculoviral IAP repeat-containing 4; X-linked inhibitor of apoptosis; IAP-3; ILP1; MIHA; ......
Chromosomal Location	Xq25
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between XIAP and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between XIAP and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
19737940	Colon Carcinoma	Inhibit immunity (T cell function)	Infection of HT29 and HCT116 cells with Adv-XIAP-shRNA led to enhanced caspase-3 activity, which was associated with increased apoptosis and reduced cell proliferation. The therapeutic effect of Adv-XIAP-shRNA was then tested in xenograft tumors in nude mice. We showed that treatment of the xenograft tumors derived from HCT116 cells with Adv-XIAP-shRNA resulted in a retardation of tumor growth, which was associated with enhanced apoptosis, increased caspase-3 activity, and reduced expression of proliferating cell nuclear antigen in the tumor tissues. Thus, Adv-XIAP-shRNA-mediated down-regulation of XIAP exerts a therapeutic effect in colon cancer by promoting apoptosis and inhibiting proliferation of colon cancer cells, and the antitumor effect of Adv-XIAP-shRNA was unlikely to be related to virus-induced immune response.
29486738	Breast Carcinoma; Melanoma	Inhibit immunity (T cell function)	IL-6, IL-8 and XIAP showed increased expressions in PTX-treated cells and this over-production effect was inhibited in TLR4-transient knockdown cells. Apoptotic cells were detected higher when PTX and CpdA were combined than PTX treatment alone. Isobologram exhibited the synergistic effect of CpdA and PTX. CpdA could significantly decrease expressions of IL-6, XIAP and IL-8, as well as excreted IL-8 levels together with reduced cancer viability after PTX treatment. The acquired TLR4-mediated PTX resistance in BCA and melanoma is explained partly by the paracrine effect of IL-6 and IL-8 released into the tumor microenvironment and over-production of anti-apoptotic protein, XIAP, in BCA cells and importantly CpdA could reduce this effect and sensitize PTX-induced apoptosis in a synergistic manner.
16868249	lymphoma	Inhibit immunity (T cell function)	Here, we aimed to develop molecular strategies to overcome the resistance of HL cells against CTL-mediated killing via granzyme B (grzB). In HL cells, grzB-induced mitochondrial release of proapoptotic Smac is blocked, which results in complete abrogation of cytotoxicity mediated by CTLs. Cytosolic expression of recombinant mature Smac enhanced caspase activity induced by grzB and restored the apoptotic response of HL cells. Similarly, down-regulation of XIAP by RNA interference markedly enhanced the susceptibility of HL cells for CTL-mediated cytotoxicity.

Summary
Symbol	XIAP
Name	X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase
Aliases	hILP; API3; BIRC4; baculoviral IAP repeat-containing 4; X-linked inhibitor of apoptosis; IAP-3; ILP1; MIHA; ......
Chromosomal Location	Xq25
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of XIAP in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	XIAP
Name	X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase
Aliases	hILP; API3; BIRC4; baculoviral IAP repeat-containing 4; X-linked inhibitor of apoptosis; IAP-3; ILP1; MIHA; ......
Chromosomal Location	Xq25
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of XIAP in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	0.003	0.991
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.374	0.808
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.272	0.819
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.076	0.84
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.254	0.884
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.153	0.947
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.142	0.725
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.208	0.904
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.09	0.962
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.594	0.57
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0.746	0.65
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.032	0.656

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of XIAP in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	3.7	3.7	0.27
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	3.7	3.7	0.314
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	4.8	4.8	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	7.7	7.7	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	11.1	11.1	0.36
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	20	20	0.357
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	0	0	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	1

Summary
Symbol	XIAP
Name	X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase
Aliases	hILP; API3; BIRC4; baculoviral IAP repeat-containing 4; X-linked inhibitor of apoptosis; IAP-3; ILP1; MIHA; ......
Chromosomal Location	Xq25
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of XIAP. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	XIAP
Name	X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase
Aliases	hILP; API3; BIRC4; baculoviral IAP repeat-containing 4; X-linked inhibitor of apoptosis; IAP-3; ILP1; MIHA; ......
Chromosomal Location	Xq25
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of XIAP. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by XIAP. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	XIAP
Name	X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase
Aliases	hILP; API3; BIRC4; baculoviral IAP repeat-containing 4; X-linked inhibitor of apoptosis; IAP-3; ILP1; MIHA; ......
Chromosomal Location	Xq25
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of XIAP. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	XIAP
Name	X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase
Aliases	hILP; API3; BIRC4; baculoviral IAP repeat-containing 4; X-linked inhibitor of apoptosis; IAP-3; ILP1; MIHA; ......
Chromosomal Location	Xq25
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of XIAP expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	XIAP
Name	X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase
Aliases	hILP; API3; BIRC4; baculoviral IAP repeat-containing 4; X-linked inhibitor of apoptosis; IAP-3; ILP1; MIHA; ......
Chromosomal Location	Xq25
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between XIAP and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	XIAP
Name	X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase
Aliases	hILP; API3; BIRC4; baculoviral IAP repeat-containing 4; X-linked inhibitor of apoptosis; IAP-3; ILP1; MIHA; ......
Chromosomal Location	Xq25
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting XIAP collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting XIAP.

ID	Name	Drug Type	Targets	#Targets
DB02628	1-[3,3-Dimethyl-2-(2-Methylamino-Propionylamino)-Butyryl]-Pyrrolidine-2-Carboxylic Acid(1,2,3,4-Tetrahydro-Naphthalen-1-Yl)-Amide	Small Molecule	XIAP	1
DB04209	Dequalinium	Small Molecule	CNGA1, KCNMA1, XIAP	3
DB04612	N-METHYLALANYL-3-METHYLVALYL-4-PHENOXY-N-(1,2,3,4-TETRAHYDRONAPHTHALEN-1-YL)PROLINAMIDE	Small Molecule	XIAP	1

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