TISIDB

Summary
Symbol	TMEM173
Name	transmembrane protein 173
Aliases	FLJ38577; NET23; MITA; MPYS; SAVI; STING; hMITA; hSTING; N-terminal methionine-proline-tyrosine-serine plasm ......
Chromosomal Location	5q31.2
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	Endoplasmic reticulum membrane Multi-pass membrane protein Mitochondrion outer membrane Multi-pass membrane protein Cell membrane Multi-pass membrane protein Cytoplasm, perinuclear region Cytoplasm Note=In response to double-stranded DNA stimulation, relocalizes to perinuclear region, where the kinase TBK1 is recruited.
Domain	PF15009 Transmembrane protein 173
Function	Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm. Acts by recognizing and binding cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced in response to DNA virus in the cytosol: upon binding of c-di-GMP or cGAMP, autoinhibition is alleviated and TMEM173/STING is able to activate both NF-kappa-B and IRF3 transcription pathways to induce expression of type I interferon and exert a potent anti-viral state. May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons. May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II). Mediates death signaling via activation of the extracellular signal-regulated kinase (ERK) pathway. Essential for the induction of IFN-beta in response to human herpes simplex virus 1 (HHV-1) infection. Exhibits 2',3' phosphodiester linkage-specific ligand recognition. Can bind both 2'-3' linked cGAMP and 3'-3' linked cGAMP but is preferentially activated by 2'-3' linked cGAMP (PubMed:26300263). ; FUNCTION: (Microbial infection) Antiviral activity is antagonized by oncoproteins, such as papillomavirus (HPV) protein E7 and adenovirus early E1A protein (PubMed:26405230). Such oncoproteins prevent the ability to sense cytosolic DNA (PubMed:26405230).

> Gene Ontology [ TOP ]
Biological Process	GO:0000060 protein import into nucleus, translocation GO:0001819 positive regulation of cytokine production GO:0002218 activation of innate immune response GO:0002230 positive regulation of defense response to virus by host GO:0002697 regulation of immune effector process GO:0002831 regulation of response to biotic stimulus GO:0006606 protein import into nucleus GO:0006913 nucleocytoplasmic transport GO:0009615 response to virus GO:0017038 protein import GO:0031349 positive regulation of defense response GO:0032092 positive regulation of protein binding GO:0032386 regulation of intracellular transport GO:0032388 positive regulation of intracellular transport GO:0032479 regulation of type I interferon production GO:0032481 positive regulation of type I interferon production GO:0032606 type I interferon production GO:0032608 interferon-beta production GO:0033157 regulation of intracellular protein transport GO:0033158 regulation of protein import into nucleus, translocation GO:0033160 positive regulation of protein import into nucleus, translocation GO:0034504 protein localization to nucleus GO:0035456 response to interferon-beta GO:0035458 cellular response to interferon-beta GO:0042306 regulation of protein import into nucleus GO:0042307 positive regulation of protein import into nucleus GO:0042990 regulation of transcription factor import into nucleus GO:0042991 transcription factor import into nucleus GO:0042993 positive regulation of transcription factor import into nucleus GO:0043330 response to exogenous dsRNA GO:0043331 response to dsRNA GO:0043393 regulation of protein binding GO:0043900 regulation of multi-organism process GO:0043903 regulation of symbiosis, encompassing mutualism through parasitism GO:0044744 protein targeting to nucleus GO:0045088 regulation of innate immune response GO:0045089 positive regulation of innate immune response GO:0046822 regulation of nucleocytoplasmic transport GO:0046824 positive regulation of nucleocytoplasmic transport GO:0050688 regulation of defense response to virus GO:0050691 regulation of defense response to virus by host GO:0050792 regulation of viral process GO:0051098 regulation of binding GO:0051099 positive regulation of binding GO:0051169 nuclear transport GO:0051170 nuclear import GO:0051222 positive regulation of protein transport GO:0051607 defense response to virus GO:0071359 cellular response to dsRNA GO:0071360 cellular response to exogenous dsRNA GO:0071407 cellular response to organic cyclic compound GO:0090316 positive regulation of intracellular protein transport GO:0098542 defense response to other organism GO:1900180 regulation of protein localization to nucleus GO:1900182 positive regulation of protein localization to nucleus GO:1902593 single-organism nuclear import GO:1903533 regulation of protein targeting GO:1903829 positive regulation of cellular protein localization GO:1904589 regulation of protein import GO:1904591 positive regulation of protein import GO:1904951 positive regulation of establishment of protein localization
Molecular Function	GO:0008134 transcription factor binding GO:0019001 guanyl nucleotide binding GO:0030551 cyclic nucleotide binding GO:0031625 ubiquitin protein ligase binding GO:0032561 guanyl ribonucleotide binding GO:0035438 cyclic-di-GMP binding GO:0044389 ubiquitin-like protein ligase binding GO:0061507 cyclic-GMP-AMP binding
Cellular Component	GO:0005741 mitochondrial outer membrane GO:0005777 peroxisome GO:0019867 outer membrane GO:0030659 cytoplasmic vesicle membrane GO:0031968 organelle outer membrane GO:0042579 microbody

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04621 NOD-like receptor signaling pathway hsa04622 RIG-I-like receptor signaling pathway hsa04623 Cytosolic DNA-sensing pathway
Reactome	R-HSA-1834949: Cytosolic sensors of pathogen-associated DNA R-HSA-3270619: IRF3-mediated induction of type I IFN R-HSA-168256: Immune System R-HSA-168249: Innate Immune System R-HSA-6798695: Neutrophil degranulation R-HSA-3134975: Regulation of innate immune responses to cytosolic DNA R-HSA-3249367: STAT6-mediated induction of chemokines R-HSA-1834941: STING mediated induction of host immune responses

> KEGG and Reactome Pathway

[ TOP ]

KEGG

hsa04621 NOD-like receptor signaling pathway
hsa04622 RIG-I-like receptor signaling pathway
hsa04623 Cytosolic DNA-sensing pathway

Reactome

R-HSA-1834949: Cytosolic sensors of pathogen-associated DNA
R-HSA-3270619: IRF3-mediated induction of type I IFN
R-HSA-168256: Immune System
R-HSA-168249: Innate Immune System
R-HSA-6798695: Neutrophil degranulation
R-HSA-3134975: Regulation of innate immune responses to cytosolic DNA
R-HSA-3249367: STAT6-mediated induction of chemokines
R-HSA-1834941: STING mediated induction of host immune responses

Summary
Symbol	TMEM173
Name	transmembrane protein 173
Aliases	FLJ38577; NET23; MITA; MPYS; SAVI; STING; hMITA; hSTING; N-terminal methionine-proline-tyrosine-serine plasm ......
Chromosomal Location	5q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between TMEM173 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 TMEM173 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
26607445	Melanoma; Colon Carcinoma	Promote immunity (T cell function)	Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer.
26964621	Lung Carcinoma	Inhibit immunity (T cell function)	Here, we show that IDO activity induced by STING activity in the tumor microenvironment (TME) promoted the growth of Lewis lung carcinoma (LLC).
25385820	Melanoma	Promote immunity (T cell function)	DCs are shown to depend on STING function in vivo to efficiently prime IFN-dependent CD8(+) T cell responses to tumor Ags.
25300859	Glioma	Promote immunity	STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment.
28436963	Melanoma; Colon Carcinoma	Promote immunity	This effect is dependent on stimulator of interferon genes (STING), but not the Toll-like receptor or the mitochondrial antiviral-signalling protein (MAVS) pathway. Here, we report a minimalist nanovaccine, comprising a simple physical mixture of an antigen and a synthetic polymeric nanoparticle, PC7A NP, which generates a strong cytotoxic T-cell response with low systemic cytokine expression. Mechanistically, the PC7A NP achieves efficient cytosolic delivery of tumour antigens to antigen-presenting cells in draining lymph nodes, leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes.
27821498	Head and Neck Squamous Cell Carcinoma	Promote immunity	Lack of induction of innate immunity through pattern-recognition receptors, such as the stimulator of interferon (IFN) genes (STING) receptor, may represent a significant barrier to the development of effective antitumor immunity. STING activation resulted in increased tumor microenvironment type 1 and type 2 IFN and greater expression of PD-1 pathway components in vivo.
27680683	Melanoma	Promote immunity (T cell function)	The innate immunoregulator STING stimulates cytokine production in response to the presence of cytosolic DNA, which can arise following DNA damage. Extrinsic STING signaling is also needed for antigen-presenting cells to stimulate antitumor T-cell immunity. Here, we show that STING signaling is recurrently suppressed in melanoma cells, where this event may enable immune escape after DNA damage. Mechanistically, STING signaling was suppressed most frequently by epigenetic silencing of either STING or the cyclic GMP-AMP synthase. Loss of STING function rendered melanoma cells unable to produce type I IFN and other immune cytokines after exposure to cytosolic DNA species.
29127039	B16 Malignant Melanoma	Promote immunity	Cyclic dinucleotides (CDNs), a potent Stimulator of Interferon Receptor (STING) agonist, are currently in phase I trials. Here we utilized biodegradable, poly(beta-amino ester) (PBAE) nanoparticles to deliver CDNs to the cytosol leading to robust immune response at >100-fold lower extracellular CDN concentrations in vitro.

Summary
Symbol	TMEM173
Name	transmembrane protein 173
Aliases	FLJ38577; NET23; MITA; MPYS; SAVI; STING; hMITA; hSTING; N-terminal methionine-proline-tyrosine-serine plasm ......
Chromosomal Location	5q31.2
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 TMEM173 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	TMEM173
Name	transmembrane protein 173
Aliases	FLJ38577; NET23; MITA; MPYS; SAVI; STING; hMITA; hSTING; N-terminal methionine-proline-tyrosine-serine plasm ......
Chromosomal Location	5q31.2
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 TMEM173 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	0.481	0.154
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.145	0.953
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0.954	0.544
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.153	0.748
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.314	0.864
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.749	0.758
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.045	0.909
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-0.148	0.924
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.221	0.901
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.79	0.677
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	0.742	0.805
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.368	0.00204

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of TMEM173 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	0	0	0	1
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	0	0	0	1
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	4.8	0	4.8	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	12.5	0	12.5	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	0	3.7	-3.7	0.415
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	7.7	-7.7	0.371
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	TMEM173
Name	transmembrane protein 173
Aliases	FLJ38577; NET23; MITA; MPYS; SAVI; STING; hMITA; hSTING; N-terminal methionine-proline-tyrosine-serine plasm ......
Chromosomal Location	5q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of TMEM173. 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	TMEM173
Name	transmembrane protein 173
Aliases	FLJ38577; NET23; MITA; MPYS; SAVI; STING; hMITA; hSTING; N-terminal methionine-proline-tyrosine-serine plasm ......
Chromosomal Location	5q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of TMEM173. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by TMEM173. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	TMEM173
Name	transmembrane protein 173
Aliases	FLJ38577; NET23; MITA; MPYS; SAVI; STING; hMITA; hSTING; N-terminal methionine-proline-tyrosine-serine plasm ......
Chromosomal Location	5q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of TMEM173. 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	TMEM173
Name	transmembrane protein 173
Aliases	FLJ38577; NET23; MITA; MPYS; SAVI; STING; hMITA; hSTING; N-terminal methionine-proline-tyrosine-serine plasm ......
Chromosomal Location	5q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of TMEM173 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	TMEM173
Name	transmembrane protein 173
Aliases	FLJ38577; NET23; MITA; MPYS; SAVI; STING; hMITA; hSTING; N-terminal methionine-proline-tyrosine-serine plasm ......
Chromosomal Location	5q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between TMEM173 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	TMEM173
Name	transmembrane protein 173
Aliases	FLJ38577; NET23; MITA; MPYS; SAVI; STING; hMITA; hSTING; N-terminal methionine-proline-tyrosine-serine plasm ......
Chromosomal Location	5q31.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting TMEM173 collected from DrugBank database.

> Drugs from DrugBank database [ TOP ]
There is no record.

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