TISIDB

Summary
Symbol	ISG15
Name	ISG15 ubiquitin-like modifier
Aliases	IFI15; G1P2; interferon, alpha-inducible protein (clone IFI-15K); IMD38; IP17; hUCRP; interferon-induced 17- ......
Chromosomal Location	1p36.33
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 Secreted Note=Exists in three distinct states: free within the cell, released into the extracellular space, or conjugated to target proteins.
Domain	PF00240 Ubiquitin family
Function	Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein. Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Can also isgylate: EIF2AK2/PKR which results in its activation, DDX58/RIG-I which inhibits its function in antiviral signaling response, EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity, UBE2N and UBE2E1 which negatively regulates their activity, IRF3 which inhibits its ubiquitination and degradation and FLNB which prevents its ability to interact with the upstream activators of the JNK cascade therby inhibiting IFNA-induced JNK signaling. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A, HIV-1 and Ebola virus. Restricts HIV-1 and ebola virus via disruption of viral budding. Inhibits the ubiquitination of HIV-1 Gag and host TSG101 and disrupts their interaction, thereby preventing assembly and release of virions from infected cells. Inhibits Ebola virus budding mediated by the VP40 protein by disrupting ubiquitin ligase activity of NEDD4 and its ability to ubiquitinate VP40. ISGylates influenza A virus NS1 protein which causes a loss of function of the protein and the inhibition of virus replication. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity.

> Gene Ontology [ TOP ]
Biological Process	GO:0000731 DNA synthesis involved in DNA repair GO:0001818 negative regulation of cytokine production GO:0002262 myeloid cell homeostasis GO:0006301 postreplication repair GO:0009615 response to virus GO:0019058 viral life cycle GO:0019079 viral genome replication GO:0019985 translesion synthesis GO:0030099 myeloid cell differentiation GO:0030218 erythrocyte differentiation GO:0031396 regulation of protein ubiquitination GO:0031397 negative regulation of protein ubiquitination GO:0032020 ISG15-protein conjugation GO:0032479 regulation of type I interferon production GO:0032480 negative regulation of type I interferon production GO:0032606 type I interferon production GO:0032609 interferon-gamma production GO:0032649 regulation of interferon-gamma production GO:0032844 regulation of homeostatic process GO:0032846 positive regulation of homeostatic process GO:0034101 erythrocyte homeostasis GO:0034340 response to type I interferon GO:0042742 defense response to bacterium GO:0043900 regulation of multi-organism process GO:0043901 negative regulation of multi-organism process GO:0043903 regulation of symbiosis, encompassing mutualism through parasitism GO:0045069 regulation of viral genome replication GO:0045071 negative regulation of viral genome replication GO:0045637 regulation of myeloid cell differentiation GO:0045639 positive regulation of myeloid cell differentiation GO:0045646 regulation of erythrocyte differentiation GO:0045648 positive regulation of erythrocyte differentiation GO:0048525 negative regulation of viral process GO:0048872 homeostasis of number of cells GO:0050792 regulation of viral process GO:0051607 defense response to virus GO:0060337 type I interferon signaling pathway GO:0071357 cellular response to type I interferon GO:0071897 DNA biosynthetic process GO:0098542 defense response to other organism GO:1903320 regulation of protein modification by small protein conjugation or removal GO:1903321 negative regulation of protein modification by small protein conjugation or removal GO:1903706 regulation of hemopoiesis GO:1903708 positive regulation of hemopoiesis GO:1903900 regulation of viral life cycle GO:1903901 negative regulation of viral life cycle
Molecular Function	GO:0031386 protein tag
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04622 RIG-I-like receptor signaling pathway
Reactome	R-HSA-168276: NS1 Mediated Effects on Host Pathways R-HSA-1169410: Antiviral mechanism by IFN-stimulated genes R-HSA-1280215: Cytokine Signaling in Immune system R-HSA-73893: DNA Damage Bypass R-HSA-73894: DNA Repair R-HSA-1643685: Disease R-HSA-168253: Host Interactions with Influenza Factors R-HSA-1169408: ISG15 antiviral mechanism R-HSA-168256: Immune System R-HSA-5663205: Infectious disease R-HSA-168254: Influenza Infection R-HSA-168249: Innate Immune System R-HSA-913531: Interferon Signaling R-HSA-909733: Interferon alpha/beta signaling R-HSA-936440: Negative regulators of RIG-I/MDA5 signaling R-HSA-168928: RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways R-HSA-5656169: Termination of translesion DNA synthesis R-HSA-110313: Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template

> KEGG and Reactome Pathway

[ TOP ]

KEGG

hsa04622 RIG-I-like receptor signaling pathway

Reactome

R-HSA-168276: NS1 Mediated Effects on Host Pathways
R-HSA-1169410: Antiviral mechanism by IFN-stimulated genes
R-HSA-1280215: Cytokine Signaling in Immune system
R-HSA-73893: DNA Damage Bypass
R-HSA-73894: DNA Repair
R-HSA-1643685: Disease
R-HSA-168253: Host Interactions with Influenza Factors
R-HSA-1169408: ISG15 antiviral mechanism
R-HSA-168256: Immune System
R-HSA-5663205: Infectious disease
R-HSA-168254: Influenza Infection
R-HSA-168249: Innate Immune System
R-HSA-913531: Interferon Signaling
R-HSA-909733: Interferon alpha/beta signaling
R-HSA-936440: Negative regulators of RIG-I/MDA5 signaling
R-HSA-168928: RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways
R-HSA-5656169: Termination of translesion DNA synthesis
R-HSA-110313: Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template

Summary
Symbol	ISG15
Name	ISG15 ubiquitin-like modifier
Aliases	IFI15; G1P2; interferon, alpha-inducible protein (clone IFI-15K); IMD38; IP17; hUCRP; interferon-induced 17- ......
Chromosomal Location	1p36.33
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between ISG15 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 ISG15 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
26122932	E7+ tumor TC-1	Promote immunity (T cell function)	Ubiquitin-like Molecule ISG15 Acts as an Immune Adjuvant to Enhance Antigen-specific CD8 T-cell Tumor Immunity.

Summary
Symbol	ISG15
Name	ISG15 ubiquitin-like modifier
Aliases	IFI15; G1P2; interferon, alpha-inducible protein (clone IFI-15K); IMD38; IP17; hUCRP; interferon-induced 17- ......
Chromosomal Location	1p36.33
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 ISG15 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	ISG15
Name	ISG15 ubiquitin-like modifier
Aliases	IFI15; G1P2; interferon, alpha-inducible protein (clone IFI-15K); IMD38; IP17; hUCRP; interferon-induced 17- ......
Chromosomal Location	1p36.33
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 ISG15 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	-1.168	0.0536
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.728	0.802
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-1.496	0.506
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.61	0.529
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.09	0.962
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	1.279	0.608
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	-0.014	0.983
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-0.321	0.797
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.199	0.894
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	1.052	0.653
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	-0.719	0.847
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.301	0.0804

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of ISG15 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	0	0	1
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	0	0	1
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	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	1
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	ISG15
Name	ISG15 ubiquitin-like modifier
Aliases	IFI15; G1P2; interferon, alpha-inducible protein (clone IFI-15K); IMD38; IP17; hUCRP; interferon-induced 17- ......
Chromosomal Location	1p36.33
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of ISG15. 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	ISG15
Name	ISG15 ubiquitin-like modifier
Aliases	IFI15; G1P2; interferon, alpha-inducible protein (clone IFI-15K); IMD38; IP17; hUCRP; interferon-induced 17- ......
Chromosomal Location	1p36.33
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of ISG15. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by ISG15. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	ISG15
Name	ISG15 ubiquitin-like modifier
Aliases	IFI15; G1P2; interferon, alpha-inducible protein (clone IFI-15K); IMD38; IP17; hUCRP; interferon-induced 17- ......
Chromosomal Location	1p36.33
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of ISG15. 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	ISG15
Name	ISG15 ubiquitin-like modifier
Aliases	IFI15; G1P2; interferon, alpha-inducible protein (clone IFI-15K); IMD38; IP17; hUCRP; interferon-induced 17- ......
Chromosomal Location	1p36.33
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of ISG15 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	ISG15
Name	ISG15 ubiquitin-like modifier
Aliases	IFI15; G1P2; interferon, alpha-inducible protein (clone IFI-15K); IMD38; IP17; hUCRP; interferon-induced 17- ......
Chromosomal Location	1p36.33
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between ISG15 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	ISG15
Name	ISG15 ubiquitin-like modifier
Aliases	IFI15; G1P2; interferon, alpha-inducible protein (clone IFI-15K); IMD38; IP17; hUCRP; interferon-induced 17- ......
Chromosomal Location	1p36.33
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting ISG15 collected from DrugBank database.

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

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