IFI16

Summary

IFI16 (interferon gamma inducible protein 16, HGNC:5395) is a protein-coding gene on chromosome 1q23.1, encoding Gamma-interferon-inducible protein 16 (Q16666). Binds double-stranded DNA.

This gene encodes a member of the HIN-200 (hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats) family of cytokines. The encoded protein contains domains involved in DNA binding, transcriptional regulation, and protein-protein interactions. The protein localizes to the nucleoplasm and nucleoli, and interacts with p53 and retinoblastoma-1. It modulates p53 function, and inhibits cell growth in the Ras/Raf signaling pathway. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3428 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 137 total
• Transcription factor: yes — 25 downstream targets (CollecTRI)
• MANE Select transcript: NM_001376587

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5395
Approved symbol	IFI16
Name	interferon gamma inducible protein 16
Location	1q23.1
Locus type	gene with protein product
Status	Approved
Aliases	IFNGIP1, PYHIN2
Ensembl gene	ENSG00000163565
Ensembl biotype	protein_coding
OMIM	147586
Entrez	3428

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 27 protein_coding, 3 retained_intron

ENST00000295809, ENST00000359709, ENST00000368131, ENST00000368132, ENST00000426592, ENST00000447473, ENST00000448393, ENST00000474473, ENST00000483916, ENST00000493884, ENST00000562225, ENST00000566111, ENST00000567661, ENST00000902828, ENST00000902829, ENST00000902830, ENST00000902831, ENST00000902832, ENST00000902833, ENST00000902834, ENST00000902835, ENST00000902836, ENST00000902837, ENST00000902838, ENST00000946383, ENST00000946384, ENST00000946385, ENST00000946386, ENST00000946387, ENST00000946388

RefSeq mRNA: 8 — MANE Select: NM_001376587 NM_001206567, NM_001364867, NM_001376587, NM_001376588, NM_001376589, NM_001376591, NM_001376592, NM_005531

CCDS: CCDS1180, CCDS58039, CCDS91079, CCDS91080

Canonical transcript exons

ENST00000295809 — 12 exons

Exon	Start	End
ENSE00001511230	159009907	159010161
ENSE00003472774	159053533	159053724
ENSE00003475029	159018229	159018651
ENSE00003481880	159045297	159045464
ENSE00003524485	159032524	159032691
ENSE00003571328	159051679	159052098
ENSE00003573471	159054821	159055151
ENSE00003590004	159015872	159015987
ENSE00003619957	159016533	159016700
ENSE00003629945	159014661	159014945
ENSE00003664980	159049432	159049599
ENSE00003791511	159020341	159020529

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 99.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 72.6087 / max 1038.1923, expressed in 1629 samples.

FANTOM5 promoters (25 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5927	42.8574	1593
5928	12.3027	1316
5930	4.5675	935
5937	4.1748	632
5919	1.9191	777
5929	1.8459	785
5936	0.7481	306
5926	0.6252	359
5922	0.5183	174
5920	0.4799	200

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	99.35	gold quality
pericardium	UBERON:0002407	99.31	gold quality
palpebral conjunctiva	UBERON:0001812	98.99	gold quality
calcaneal tendon	UBERON:0003701	98.72	gold quality
lymph node	UBERON:0000029	98.69	gold quality
superficial temporal artery	UBERON:0001614	98.54	gold quality
vena cava	UBERON:0004087	98.49	gold quality
nasal cavity mucosa	UBERON:0001826	98.48	gold quality
spleen	UBERON:0002106	98.46	gold quality
monocyte	CL:0000576	98.36	gold quality
penis	UBERON:0000989	98.36	gold quality
gingiva	UBERON:0001828	98.36	gold quality
leukocyte	CL:0000738	98.33	gold quality
mononuclear cell	CL:0000842	98.33	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.33	gold quality
nasal cavity epithelium	UBERON:0005384	98.32	gold quality
gingival epithelium	UBERON:0001949	98.28	gold quality
blood	UBERON:0000178	98.24	gold quality
peritoneum	UBERON:0002358	98.22	gold quality
omental fat pad	UBERON:0010414	98.22	gold quality
gall bladder	UBERON:0002110	98.21	gold quality
vermiform appendix	UBERON:0001154	98.20	gold quality
tendon of biceps brachii	UBERON:0008188	98.13	gold quality
tendon	UBERON:0000043	98.09	gold quality
caecum	UBERON:0001153	98.05	gold quality
granulocyte	CL:0000094	98.02	gold quality
synovial joint	UBERON:0002217	98.01	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.01	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.97	gold quality
mammalian vulva	UBERON:0000997	97.88	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-8271	yes	529.05
E-MTAB-3929	yes	254.22
E-CURD-112	yes	39.67
E-HCAD-10	yes	25.43
E-CURD-122	yes	22.33
E-HCAD-31	yes	21.60
E-MTAB-5061	yes	11.26
E-MTAB-10042	yes	9.96
E-GEOD-83139	yes	7.88
E-ENAD-27	yes	6.55
E-GEOD-130148	yes	6.25
E-CURD-88	yes	5.70
E-CURD-119	yes	5.04
E-MTAB-7249	no	1111.21
E-MTAB-7052	no	741.19

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

25 targets.

Target	Regulation
APOD
BGLAP
BRCA1	Unknown
CDKN1A	Unknown
CFD
ESR1
ICAM1	Repression
IFNA1
IFNB1
IFNG
IFNL3
LPL
MTA1
MYC	Repression
MYD88
OAS1
PPARG
RB1
RIGI
SP1
SUPT7L
TERT
TP53	Unknown
TPM1
WT1	Activation

Upstream regulators (CollecTRI, top): AR, ESR1, FOXP3, JUN, NR3C1, SP1, STAT3, TP53

miRNA regulators (miRDB)

22 targeting IFI16, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-4423-3P	97.98	69.66	912
HSA-MIR-3159	97.94	66.79	1098
HSA-MIR-3650	97.88	64.89	693
HSA-MIR-3684	96.90	67.51	293
HSA-MIR-382-5P	96.71	65.90	762

Literature-anchored findings (GeneRIF, showing 40)

• IFI16 expression is seen not only in hematopoietic cells but also in adult stratified squamous epithelia, especially parabasal cells in proliferating compartments, decreasing in more differentiated suprabasal layers, suggesting a role in differentiation. (PMID:12184920)
• transcriptional mechanisms of IFI 16 gene regulation (PMID:12682910)
• increased levels of IFI 16 in prostate epithelial cells contribute to senescence-associated irreversible cell growth arrest. (PMID:12894224)
• IFI16 has a role in modulating p53 function and regulating its target gene in the control of cell cycle regulation (PMID:12925527)
• HUVEC infection with TO-IFI16 virus suppressed endothelial migration, invasion and formation of capillary-like structures in vitro. In parallel, sustained IFI16 expression inhibited HUVEC cell cycle progression. (PMID:14729471)
• IFI16 has a role in activation of p53 induced by ionizing radiation (PMID:14990579)
• This study is the first expression analysis of the IFN-inducible IFI16 gene in head and neck squamous cell carcinomas. (PMID:15569046)
• IFI16 is an essential growth-specific effector of the cell-extrinsic growth inhibitory pathway of Ras/Raf signaling in MTC cells (PMID:15572361)
• a novel role of IFI16 in the signal transduction pathway that leads to p53 activation by oxidative stress in endothelial cells (PMID:15728246)
• IFI16 protein bound to androgen receptor (AR) in a ligand-dependent manner and the DNA-binding domain of the AR was sufficient to bind IFI16. (PMID:16494870)
• Histone deacetylase-dependent transcriptional silencing of the IFI16 gene in prostate epithelial cells contributes to the development of prostate cancer. (PMID:17339605)
• IFI16 appears to be involved in maintaining the normal growth of epithelial cells, whereas its downregulation may contribute to uncontrolled cell proliferation and tumorigenesis. (PMID:17510972)
• IFI16 is a novel regulator of endothelial proinflammatory activity (PMID:17699163)
• IFI16 is involved in DNA damage signaling and cell cycle checkpoint [review] (PMID:17981541)
• loss of IFI16 activates p53 checkpoint through NBS1-DNA-PKcs pathway (PMID:17981542)
• IFI16 protein has roles in human cancers and autoimmune diseases (PMID:17981573)
• Ifi204 is a regulator of monocyte/macrophage differentiation and make possible a connection with other myeloid regulators [review] (PMID:17981596)
• WT1 induction led to strong induction of IFI16 expression and its promoter activity was responsive to the WT1 protein. (PMID:18231640)
• results indicate that IFI16-HIN200 is an RPA-like, OB-fold, nucleic acid-binding protein that binds to ssDNA with higher affinity than to dsDNA, recognizes ssDNA in the same orientation as RPA, oligomerizes upon ssDNA binding, wraps and stretches ssDNA (PMID:18472023)
• increased expression levels may contribute to lupus and other autoimmune diseases susceptibility (PMID:18598717)
• observations provide support for the idea that up-regulation of IFI16 expression by p53 and functional interactions between IFI16 protein and p53 contribute to cellular senescence. (PMID:18974396)
• IFI16 and NM23/NDPK are simultaneously bound in vivo to the promoters of the oncogene cMYC and of P53 (PMID:19170058)
• IFI16 mediates ICAM-1 stimulation by TNF-alpha through the NF-kappaB pathway, thus reinforcing the role of the IFI16 molecule in the inflammation process. (PMID:19338980)
• IFI16 exerts in vivo anti-tumoral activity by promoting apoptosis of tumor cells. (PMID:19553003)
• IFI16 was expressed in both the hepatocellular and inflammatory compartments in the liver allograft with acute cellular rejection. (PMID:19635103)
• IFI 16 may act as an endogenous regulator of telomerase activity (PMID:19885868)
• data demonstrated that increased levels of IFI16 protein in HDFs down-regulate the expression of hTERT gene (PMID:20052289)
• IFI16 may be an essential downstream target of DLK1 in hepatocellular carcinomas (HCC) cells and required for DLK1-induced cell proliferation. (PMID:20214740)
• promotes apoptosis in endothelial cells (PMID:20488664)
• Cytomegalovirus pUL83 recruits human IFI16 to the major immediate-early promoter, and IFI16 binding at the promoter is dependent upon the presence of pUL83. (PMID:20504932)
• IFI16, a PYHIN protein, as an intracellular DNA sensor that mediates the induction of interferon-beta (PMID:20890285)
• Both HIN domains of interferon, gamma-inducible protein 16 are capable of enhancing p53-DNA complex formation and transcriptional activation via distinctive means. (PMID:21397192)
• Differential roles for the interferon-inducible IFI16 and AIM2 innate immune sensors for cytosolic DNA in cellular senescence of human fibroblasts (PMID:21471287)
• Glucose restriction or treatment of human diploid fibroblasts (HDFs) with the activators of the AMPK/p53 pathway induced the expression of IFI16 protein. (PMID:21573174)
• The authors demonstrate that during KSHV infection of endothelial cells, interferon gamma-inducible protein 16 (IFI16) interacts with the adaptor molecule ASC and procaspase-1 to form a functional inflammasome. (PMID:21575908)
• type-I and type-II IFNs induce the expression of IFI16, AIM2, and inflammasome proteins to various extents in THP-1 cells and the expression of IFI16 protein in THP-1 cells suppresses the activation of caspase-1 by the AIM2 and NLRP3 inflammasomes (PMID:22046441)
• data implicate IFI16 as a novel restriction factor against HCMV replication and provide new insight into the physiological functions of the IFN-inducible gene IFI16 as a viral restriction factor. (PMID:22291595)
• expression of AIM2 and IFI16 may have oncogenic activities in the OSCC cells that have inactivated the p53 system. (PMID:22320325)
• crystal structures of AIM2 and IFI16 HIN domains in complex with double-stranded (ds) DNA (PMID:22483801)
• this novel DNA-binding property of IFI16 protein to scDNA and cruciform structures may play critical roles in its tumor suppressor function. (PMID:22618232)

Cross-species orthologs

0 orthologs

Paralogs (3): MNDA (ENSG00000163563), PYHIN1 (ENSG00000163564), AIM2 (ENSG00000163568)

Protein

Protein identifiers

Gamma-interferon-inducible protein 16 — Q16666 (reviewed: Q16666)

Alternative names: Interferon-inducible myeloid differentiation transcriptional activator

All UniProt accessions (6): Q16666, H3BM18, H3BR65, H3BR88, H3BVE6, X6RHM1

UniProt curated annotations — full annotation on UniProt →

Function. Binds double-stranded DNA. Binds preferentially to supercoiled DNA and cruciform DNA structures. Seems to be involved in transcriptional regulation. May function as a transcriptional repressor. Could have a role in the regulation of hematopoietic differentiation through activation of unknown target genes. Controls cellular proliferation by modulating the functions of cell cycle regulatory factors including p53/TP53 and the retinoblastoma protein. May be involved in TP53-mediated transcriptional activation by enhancing TP53 sequence-specific DNA binding and modulating TP53 phosphorylation status. Seems to be involved in energy-level-dependent activation of the ATM/ AMPK/TP53 pathway coupled to regulation of autophagy. May be involved in regulation of TP53-mediated cell death also involving BRCA1. May be involved in the senescence of prostate epithelial cells. Involved in innate immune response by recognizing viral dsDNA in the cytosol and probably in the nucleus. After binding to viral DNA in the cytoplasm recruits TMEM173/STING and mediates the induction of IFN-beta. Has anti-inflammatory activity and inhibits the activation of the AIM2 inflammasome, probably via association with AIM2. Proposed to bind viral DNA in the nucleus, such as of Kaposi’s sarcoma-associated herpesvirus, and to induce the formation of nuclear caspase-1-activating inflammasome formation via association with PYCARD. Inhibits replication of herpesviruses such as human cytomegalovirus (HCMV) probably by interfering with promoter recruitment of members of the Sp1 family of transcription factors. Necessary to activate the IRF3 signaling cascade during human herpes simplex virus 1 (HHV-1) infection and promotes the assembly of heterochromatin on herpesviral DNA and inhibition of viral immediate-early gene expression and replication. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Isoform that specifically inhibits the AIM2 inflammasome. Binds double-stranded DNA (dsDNA) in the cytoplasm, impeding its detection by AIM2. Also prevents the interaction between AIM2 and PYCARD/ASC via its interaction with AIM2, thereby inhibiting assembly of the AIM2 inflammasome. This isoform also weakly induce production of type I interferon-beta (IFNB1) via its interaction with STING1.

Subunit / interactions. Forms homooligomers; isoform 2 can self-associate or associate with isoform 1 or isoform 3. Interacts with TMEM173, AIM2, PYCARD and CASP1. Interacts with BRCA1, TP53, E2F1, RB1 and SP1. Interacts with MTA1. Interacts with PYDC5. Interacts with AIM2; preventing the interaction between AIM2 and PYCARD/ASC. Interacts with STING1.

Subcellular location. Nucleus. Cytoplasm Cytoplasm.

Tissue specificity. Expressed in peripheral blood leukocytes, fibroblasts and lymphoid cells. Present in myeloid precursors (CD34+) and throughout monocyte development, but its expression is down-regulated in erythroid and polymorphonuclear precursor cells. Present in prostate, ovary and breast (at protein level). Widely expressed.

Post-translational modifications. Ubiquitinated by human herpes simplex virus 1 (HHV-1) ICP0 protein; leading to degradation by the proteasome. Lysine acetylation in the multipartite nuclear localization signal (NLS) regulates the subcellular location. In vitro can be acetylated by p300/EP300 coupled to cytoplasmic localization. Phosphorylated on Ser and Thr. Isoform 3 seems to show a minor degree of complex carbohydrate addition.

Domain organisation. The HIN-200 domains mediates dsDNA binding via electrostatic interactions.

Induction. Strongly induced by IFNG/IFN-gamma and, to a lesser extent, by alpha interferon. In HL-60 cells, maximum induction by IFNG/IFN-gamma occurs within 12 hours whereas, for IFN-alpha, only 10-fold induction was observed after 36 hours. Induced in vitro by dimethylsulfoxide, retinoic acid and 1,25 dihydroxyvitamin D3. Induced in monocytes by IFN-alpha and viral dsDNA. Induced by glucose restriction. By interferon-beta (IFNB1).

Miscellaneous. Major isoform.

Similarity. Belongs to the HIN-200 family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q16666-1	1, IFI 16A	yes
Q16666-2	2, IFI 16B
Q16666-3	3, IFI 16C
Q16666-6	4
Q16666-8	IFI16-beta

RefSeq proteins (8): NP_001193496, NP_001351796, NP_001363516, NP_001363517, NP_001363518, NP_001363520, NP_001363521, NP_005522 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004020	DAPIN	Domain
IPR004021	HIN200/IF120x	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR040205	HIN-200	Family

Pfam: PF02758, PF02760

UniProt features (114 total): strand 28, mutagenesis site 20, modified residue 16, helix 9, sequence variant 7, cross-link 5, splice variant 5, sequence conflict 5, short sequence motif 4, turn 4, region of interest 4, domain 3, compositionally biased region 3, chain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
8X70	X-RAY DIFFRACTION	1.7
3RLO	X-RAY DIFFRACTION	1.8
2OQ0	X-RAY DIFFRACTION	2
3RLN	X-RAY DIFFRACTION	2.25
3B6Y	X-RAY DIFFRACTION	2.35
3RNU	X-RAY DIFFRACTION	2.5
4QGU	X-RAY DIFFRACTION	2.54
9LJI	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16666-F1	69.11	0.42

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (21): 45, 95, 99, 106, 128, 153, 168, 174, 214, 444, 451, 561, 575, 598, 614, 780, 116, 128, 561, 561 …

Mutagenesis-validated functional residues (20):

Position	Phenotype
96–100	predominant cytoplasmic localization.
99	predominant cytoplasmic, reduces nuclear localization (mimics non-acetylated state).
99	minor effect on nuclear localization (mimics acetylated state).
128–131	predominant nuclear, some cytoplasmic localization.
128	predominant cytoplasmic, reduces nuclear localization (mimics non-acetylated state).
128	minor effect on nuclear localization (mimics acetylated state).
134–136	mostly nuclear, minor cytoplasmic localization.
140–143	mostly nuclear, minor cytoplasmic localization.
218	abolishes tp53-mediated transcriptional activation; when associated with a-267.
222	abolishes tp53-mediated transcriptional activation; when associated with a-272.
267	abolishes tp53-mediated transcriptional activation; when associated with a-218.
272	abolishes tp53-mediated transcriptional activation; when associated with a-222.
627	impairs dna binding; when associated with a-663; a-667; a-670; a-674; a-732; a-734 and a-759.
663	impairs dna binding; when associated with a-627; a-667; a-670; a-674; a-732; a-734 and a-759.
667	impairs dna binding; when associated with a-627; a-663; a-670; a-674; a-732; a-734 and a-759.
670	impairs dna binding; when associated with a-627; a-663; a-667; a-674; a-732; a-734 and a-759.
674	impairs dna binding; when associated with a-627; a-663; a-667; a-670; a-732; a-734 and a-759.
732	impairs dna binding; when associated with a-627; a-663; a-667; a-670; a- 674; a-734 and a-759.
734	impairs dna binding; when associated with a-627; a-663; a-667; a-670; a- 674; a-732 and a-759.
759	impairs dna binding; when associated with a-627; a-663; a-667; a-670; a- 674; a-732 and a-734.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1834941	STING mediated induction of host immune responses
R-HSA-3270619	IRF3-mediated induction of type I IFN

MSigDB gene sets: 445 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, MODULE_52, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, GOBP_REGULATION_OF_AUTOPHAGY, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP

GO Biological Process (26): negative regulation of transcription by RNA polymerase II (GO:0000122), positive regulation of cytokine production (GO:0001819), activation of innate immune response (GO:0002218), autophagy (GO:0006914), inflammatory response (GO:0006954), regulation of autophagy (GO:0010506), myeloid cell differentiation (GO:0030099), monocyte differentiation (GO:0030224), positive regulation of interleukin-1 beta production (GO:0032731), cellular response to interferon-beta (GO:0035458), cellular response to glucose starvation (GO:0042149), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), negative regulation of DNA binding (GO:0043392), negative regulation of viral genome replication (GO:0045071), innate immune response (GO:0045087), negative regulation of gene expression, epigenetic (GO:0045814), negative regulation of innate immune response (GO:0045824), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of inflammatory response (GO:0050727), defense response to virus (GO:0051607), cellular response to ionizing radiation (GO:0071479), intrinsic apoptotic signaling pathway by p53 class mediator (GO:0072332), negative regulation of AIM2 inflammasome complex assembly (GO:0140972), immune system process (GO:0002376), apoptotic process (GO:0006915)

GO Molecular Function (6): double-stranded DNA binding (GO:0003690), RNA binding (GO:0003723), transcription factor binding (GO:0008134), identical protein binding (GO:0042802), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), nuclear speck (GO:0016607)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cytosolic sensors of pathogen-associated DNA	1
STING mediated induction of host immune responses	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
DNA binding	2
nucleic acid binding	2
protein binding	2
nuclear lumen	2
negative regulation of DNA-templated transcription	1
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
activation of immune response	1
positive regulation of innate immune response	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
defense response	1
autophagy	1
regulation of catabolic process	1
hemopoiesis	1
cell differentiation	1
myeloid leukocyte differentiation	1
mononuclear cell differentiation	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
response to interferon-beta	1
cellular response to cytokine stimulus	1
cellular response to starvation	1
intrinsic apoptotic signaling pathway in response to DNA damage	1
intrinsic apoptotic signaling pathway by p53 class mediator	1
negative regulation of binding	1
regulation of DNA binding	1
viral genome replication	1
regulation of viral genome replication	1
negative regulation of viral process	1
immune response	1
defense response to symbiont	1
negative regulation of gene expression	1

Protein interactions and networks

STRING

2584 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IFI16	TP53	P04637	971
IFI16	MEFV	O15553	929
IFI16	NLRC4	Q9NPP4	927
IFI16	AIM2	O14862	917
IFI16	PYCARD	Q9ULZ3	888
IFI16	CGAS	Q8N884	886
IFI16	BRCA1	P38398	882
IFI16	CASP1	P29466	881
IFI16	NLRP3	Q96P20	862
IFI16	NLRP1	Q9C000	819
IFI16	TBK1	Q9UHD2	817
IFI16	DDX41	Q9UJV9	808
IFI16	NLRP12	P59046	798
IFI16	NLRP6	P59044	775
IFI16	IRF7	Q92985	771

IntAct

50 interactions, top by confidence:

A	B	Type	Score
MORF4L1	SIN3B	psi-mi:“MI:0914”(association)	0.730
BRCA1	IFI16	psi-mi:“MI:0915”(physical association)	0.560
IFI16	BRCA1	psi-mi:“MI:0403”(colocalization)	0.560
IFI16	BRCA1	psi-mi:“MI:0915”(physical association)	0.560
BRCA1	IFI16	psi-mi:“MI:0403”(colocalization)	0.560
STING1	IFI16	psi-mi:“MI:0915”(physical association)	0.520
IFI16	AR	psi-mi:“MI:0915”(physical association)	0.520
AR	IFI16	psi-mi:“MI:0915”(physical association)	0.520
IFI16	TP53	psi-mi:“MI:0915”(physical association)	0.490
TP53	IFI16	psi-mi:“MI:0915”(physical association)	0.490
IFI16	DHX58	psi-mi:“MI:0915”(physical association)	0.400
Sting1	IFI16	psi-mi:“MI:0915”(physical association)	0.400
IFI16	SP1	psi-mi:“MI:0915”(physical association)	0.400
NOTCH1	CNOT1	psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
ZBTB18	DNASE1L1	psi-mi:“MI:0914”(association)	0.350
BMI1	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
BMI1	MEIS3P1	psi-mi:“MI:0914”(association)	0.350
RYBP	FAM186A	psi-mi:“MI:0914”(association)	0.350

BioGRID (980): AR (Affinity Capture-Western), AR (Reconstituted Complex), IFI16 (Affinity Capture-Western), TMEM173 (Reconstituted Complex), Tmem173 (Reconstituted Complex), IFI16 (Affinity Capture-RNA), ACADVL (Affinity Capture-MS), ACIN1 (Affinity Capture-MS), ADAR (Affinity Capture-MS), ADD1 (Affinity Capture-MS), AHCTF1 (Affinity Capture-MS), ASCC3 (Affinity Capture-MS), BAZ1B (Affinity Capture-MS), BAZ2A (Affinity Capture-MS), BOP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0J9YX57, A1A5P9, A2A368, A2A9R3, A8MXT2, B2KFW1, O15479, O15480, O15481, O15553, P0C6Y7, P10073, P17040, P25233, P43355, P43356, P43357, P43358, P43360, P43362, P43363, P43364, P43366, Q13342, Q16666, Q4R998, Q5PPP4, Q5RD14, Q6AY37, Q6PCZ4, Q8BQR7, Q8IWY8, Q8IX06, Q8N660, Q8N7X4, Q8TD90, Q96DU7, Q96LZ2, Q96M61, Q99608

Diamond homologs: D0QMC3, O14862, O35368, P0DOV1, P0DOV2, P41218, Q16666, Q3V3Q4, Q504N7, Q5RD14, Q6K0P9, Q8BV49, Q8CGE8, Q8SPH9, Q91VJ1, Q9R002, W6CW81

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CSNK2A1	“up-regulates activity”	IFI16	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 47 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
in utero embryonic development	7	14.8×	8e-05
regulation of cell cycle	5	11.0×	8e-03
positive regulation of gene expression	9	10.2×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

137 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	97
Likely benign	15
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1577 predictions. Top by Δscore:

Variant	Effect	Δscore
1:159010157:GTGAG:G	donor_gain	1.0000
1:159010158:TGAG:T	donor_gain	1.0000
1:159010159:GAG:G	donor_gain	1.0000
1:159010159:GAGG:G	donor_gain	1.0000
1:159010162:G:GG	donor_gain	1.0000
1:159010162:GTGA:G	donor_loss	1.0000
1:159015840:A:AG	acceptor_gain	1.0000
1:159015840:ATT:A	acceptor_gain	1.0000
1:159015840:ATTG:A	acceptor_gain	1.0000
1:159015841:T:G	acceptor_gain	1.0000
1:159015842:T:TA	acceptor_gain	1.0000
1:159020336:TACA:T	acceptor_loss	1.0000
1:159020339:A:AG	acceptor_gain	1.0000
1:159020339:A:C	acceptor_loss	1.0000
1:159020340:G:GA	acceptor_gain	1.0000
1:159020340:GA:G	acceptor_gain	1.0000
1:159020340:GAA:G	acceptor_gain	1.0000
1:159020340:GAAA:G	acceptor_gain	1.0000
1:159020444:GAGA:G	donor_gain	1.0000
1:159020526:CCAG:C	donor_loss	1.0000
1:159020528:AG:A	donor_loss	1.0000
1:159020529:GG:G	donor_loss	1.0000
1:159020530:G:GA	donor_loss	1.0000
1:159020531:T:A	donor_loss	1.0000
1:159051676:A:AG	acceptor_gain	1.0000
1:159051676:AAGTT:A	acceptor_gain	1.0000
1:159051677:A:G	acceptor_gain	1.0000
1:159052064:G:GT	donor_gain	1.0000
1:159053632:G:GT	donor_gain	1.0000
1:159053691:G:GT	donor_gain	1.0000

AlphaMissense

5255 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:159051884:T:C	F624S	0.997
1:159018370:G:C	A231P	0.996
1:159051817:G:C	A602P	0.996
1:159018437:T:C	F253S	0.995
1:159051818:C:A	A602D	0.995
1:159051883:T:C	F624L	0.995
1:159051885:C:A	F624L	0.995
1:159051885:C:G	F624L	0.995
1:159053645:T:C	L733P	0.995
1:159053659:T:C	F738L	0.995
1:159053661:T:A	F738L	0.995
1:159053661:T:G	F738L	0.995
1:159053713:A:C	S756R	0.995
1:159053715:T:A	S756R	0.995
1:159053715:T:G	S756R	0.995
1:159020518:A:C	S384R	0.994
1:159020520:T:A	S384R	0.994
1:159020520:T:G	S384R	0.994
1:159051811:T:C	F600L	0.994
1:159051813:T:A	F600L	0.994
1:159051813:T:G	F600L	0.994
1:159051934:T:C	F641L	0.994
1:159051936:C:A	F641L	0.994
1:159051936:C:G	F641L	0.994
1:159053651:T:C	L735P	0.994
1:159018364:T:C	F229L	0.993
1:159018366:T:A	F229L	0.993
1:159018366:T:G	F229L	0.993
1:159052084:T:C	F691L	0.993
1:159052086:T:A	F691L	0.993

dbSNP variants (sampled 300 via entrez): RS1000060733 (1:159042486 C>A), RS1000062422 (1:158999364 G>A), RS1000100963 (1:159027065 G>A), RS1000147252 (1:159030040 G>A,C), RS1000235202 (1:159005918 A>C), RS1000401903 (1:159024997 T>G), RS1000468405 (1:159018626 T>C), RS1000490051 (1:159029680 T>G), RS1000535360 (1:159050959 C>T), RS1000629897 (1:159037155 G>A), RS1000651478 (1:159051261 G>A), RS1000684083 (1:159035968 G>C,T), RS1000690188 (1:159024870 A>G), RS1000693519 (1:159035683 C>A), RS1000751239 (1:159031291 C>T)

Disease associations

OMIM: gene MIM:147586 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000987_15	Celiac disease or Rheumatoid arthritis	8.000000e-07
GCST001650_1	C-reactive protein	1.000000e-37
GCST001650_11	C-reactive protein	3.000000e-10
GCST001650_8	C-reactive protein	4.000000e-73
GCST001762_657	Obesity-related traits	1.000000e-06
GCST002743_1	Neutrophil count in HIV-infection	3.000000e-06
GCST003484_4	Periodontal disease-related phenotype (Socransky)	3.000000e-08
GCST90002389_71	Lymphocyte percentage of white cells	2.000000e-12
GCST90002399_9	Neutrophil percentage of white cells	3.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004458	C-reactive protein measurement
EFO:0003939	energy intake
EFO:0004833	neutrophil count
EFO:0007780	periodontal measurement
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Absent in melanoma (AIM)-like receptors (ALRs)

CTD chemical–gene interactions

88 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression, increases expression, affects cotreatment	4
Arsenic Trioxide	decreases expression, increases expression, increases response to substance, affects cotreatment	4
Tretinoin	affects cotreatment, increases expression, affects expression	4
Valproic Acid	decreases expression, decreases methylation, increases expression, affects expression	4
Cyclosporine	decreases expression, increases expression, affects cotreatment	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	3
Nickel	decreases expression, increases expression	3
bisphenol A	increases expression, decreases expression	2
belinostat	affects cotreatment, increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Estradiol	affects expression, increases expression	2
Lipopolysaccharides	increases expression, affects response to substance	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
GSK-J4	increases expression	1
TAK-243	increases sumoylation	1
2,4,6-tribromophenol	increases expression	1
testosterone enanthate	affects expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, decreases expression	1
lead acetate	decreases expression	1
methylselenic acid	increases expression	1
decabromobiphenyl ether	increases expression	1
tetrabromobisphenol A	increases expression	1
manganese chloride	increases expression, increases abundance	1
ochratoxin A	decreases acetylation, decreases expression	1
cadmium acetate	decreases expression	1
cupric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A8AU	THP1-Dual KO-IFI16	Cancer cell line	Male
CVCL_B1FP	Abcam A-549 IFI16 KO 1	Cancer cell line	Male
CVCL_B2N8	Abcam A-549 IFI16 KO 2	Cancer cell line	Male
CVCL_E1G7	Abcam Jurkat IFI16 KO	Cancer cell line	Male
CVCL_SS11	HAP1 IFI16 (-) 1	Cancer cell line	Male
CVCL_SS12	HAP1 IFI16 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.