{"gene":"IFI27","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2001,"finding":"ISG12/IFI27 protein localizes to the nuclear envelope (nuclear membrane), as demonstrated by baculovirus-expressed and FLAG-tagged recombinant ISG12 sedimentation in nuclear envelope fractions and immunocytochemical detection in IFN-alpha-treated HeLa cells.","method":"Subcellular fractionation of baculovirus-expressed and FLAG-tagged recombinant protein in HEK293 cells; immunocytochemistry in HeLa cells treated with IFN-alpha","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with two orthogonal methods (fractionation + immunocytochemistry), single lab","pmids":["11722583"],"is_preprint":false},{"year":2013,"finding":"ISG12 (IFI27) directly interacts with nuclear receptors (NRs) and acts as a co-factor stimulating nuclear export of NRs, thereby reducing the anti-inflammatory potential of NRs such as NR4A1. ISG12-deficient mice showed prolonged survival and reduced IL-6 levels in experimental sepsis, and this phenotype was restored in ISG12/NR4A1 double-deficient mice, placing ISG12 upstream of NR4A1 in innate immune regulation.","method":"ISG12-knockout mice in cecal ligation and puncture (CLP) and endotoxemia models; in vitro peritoneal macrophage experiments; genetic epistasis with NR4A1 double-knockout mice; direct interaction assay with NRs","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with double-knockout rescue, in vivo and in vitro experiments, single lab","pmids":["23747037"],"is_preprint":false},{"year":2015,"finding":"IFI27 knockdown in keratinocytes reduces proliferation and causes S-phase arrest associated with increased Tyr15 phosphorylation of CDK1, reduced CDC25B, reduced formation of cyclin A/CDK1 complex (demonstrated by co-immunoprecipitation), and activation of p53 (Ser15 phosphorylation) with increased p21 expression. EGF stabilizes IFI27 protein by prolonging its half-life.","method":"siRNA knockdown and overexpression in keratinocytes; MTT assay; flow cytometry; co-immunoprecipitation of cyclin A/CDK1; Western blot; in vivo topical siRNA in imiquimod-induced psoriasis mouse model","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KD/KO with defined cellular and molecular phenotypes, in vivo validation, single lab","pmids":["25664647"],"is_preprint":false},{"year":2016,"finding":"Full-length ISG12A/IFI27 protein sensitizes cells to TNF-alpha- and gossypol-induced apoptosis; shorter ISG12A variants directly induce apoptosis in HEK293 cells. ISG12A co-immunoprecipitates with Bcl-2, and apoptotic effects are reduced in Bcl-2-expressing cells. Two putative BH3-like motifs in the ISG12 motif are implicated. Full-length ISG12A forms homodimers suggesting a role in pore formation. ISG12A, its variants, and ISG12B localize to mitochondria.","method":"Overexpression in HEK293 cells; BH3 mutagenesis; co-immunoprecipitation with Bcl-2; mitochondrial localization by subcellular fractionation/imaging; apoptosis assays in Bcl-2-expressing cells","journal":"Biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — Co-IP, site-directed mutagenesis of BH3 motifs, subcellular fractionation, multiple orthogonal methods in single study","pmids":["27673746"],"is_preprint":false},{"year":2018,"finding":"Ifi27 protein localizes to mitochondria in adipocytes. Knockdown of Ifi27 reduces expression of TCA cycle key enzymes, electron transport chain subunits, and Ucp1 in brown and beige adipocytes, and blocks beta3-adrenergic agonist-induced browning of subcutaneous white fat. Ifi27 expression is induced by beta3-adrenergic activation in adipose tissue.","method":"Mitochondrial localization by imaging/fractionation; siRNA knockdown; overexpression in brown adipocytes; in vivo beta3-adrenergic agonist treatment; RT-qPCR and Western blot for TCA/ETC/Ucp1 markers","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization, KD and OE with defined molecular phenotypes, single lab, multiple orthogonal methods","pmids":["29730295"],"is_preprint":false},{"year":2020,"finding":"IFI27/ISG12 interacts with estrogen receptor alpha (ERα) and facilitates the interaction between ERα and CRM1/XPO1, promoting nuclear export of ERα to the cytoplasm, thereby attenuating ERα transactivation activity and expression of ERα-dependent genes. IFI27 overexpression reduces MCF-7 cell proliferation and migration.","method":"Co-immunoprecipitation of IFI27 with ERα and CRM1/XPO1; overexpression in MCF-7 breast cancer cells; reporter assay for ERα transactivation; 2D/3D proliferation assays; wound-healing migration assay","journal":"Frontiers in endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional overexpression assays, single lab, multiple orthogonal methods","pmids":["33117284"],"is_preprint":false},{"year":2021,"finding":"ATF3 transcription factor binds the promoter regions of IFI27 (and IFI6) as shown by ChIP assay, and negatively regulates IFI27 expression. Loss of ATF3 upregulates IFI27 and promotes TSCC cell growth and migration; IFI27 knockdown blocks the growth/migration induced by ATF3 deletion, and IFI27 overexpression counteracts ATF3 overexpression-mediated inhibition.","method":"ChIP assay; RNA-seq; gain- and loss-of-function of ATF3 in four TSCC cell lines; siRNA knockdown of IFI27; in vivo mouse model","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP showing direct promoter binding, multiple cell lines, in vivo rescue, multiple orthogonal methods","pmids":["33539340"],"is_preprint":false},{"year":2022,"finding":"PABPC1 interacts with eIF4G to increase the stability of IFI27 mRNA by competing with RNA exosomes, activating the IFN/IFI27 signaling pathway to enhance ESCC cell proliferation and invasion.","method":"Co-immunoprecipitation of PABPC1 with eIF4G; mRNA stability assays; PABPC1 overexpression/knockdown in ESCC cells; in vitro and in vivo proliferation/invasion assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, mRNA stability assay, functional KD/OE, single lab","pmids":["35346324"],"is_preprint":false},{"year":2023,"finding":"IFI27 counteracts innate immune responses triggered by cytoplasmic RNA recognition after influenza A virus, SARS-CoV-2, Sendai virus infections, and dsRNA transfection. IFI27 interacts with nucleic acids and with RIG-I (most likely RNA-mediated), and this interaction impairs RIG-I activation. IFI27 has a positive effect on IAV and SARS-CoV-2 replication in vitro and in vivo.","method":"Co-immunoprecipitation of IFI27 with RIG-I; IFI27 knockdown and overexpression cells; viral infection models (IAV, SARS-CoV-2, SeV); dsRNA transfection; in vivo experiments; innate immune response assays","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with RIG-I, KD/OE with defined antiviral phenotype, multiple viral systems, single lab","pmids":["37187533"],"is_preprint":false},{"year":2023,"finding":"IFI27 is required for cristae morphogenesis and sustains succinate dehydrogenase (SDH) function and fatty acid oxidation in brown adipocytes. IFI27 physically binds SDHB and HADHA (identified by interaction mapping). IFI27 links SDHB to chaperone TRAP1, shielding SDHB from oxidative damage-triggered degradation. IFI27 also increases HADHA catalytic activity in beta-oxidation. Ifi27-knockout brown fat shows reduced SDH levels, impaired fatty acid oxidation, impaired oxygen consumption and defective thermogenesis.","method":"IFI27 protein interaction mapping; co-immunoprecipitation of IFI27 with SDHB, HADHA, TRAP1; Ifi27-knockout mice; oxygen consumption assay; beta-oxidation assay; cold challenge thermogenesis model","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — physical interaction mapping, Co-IP, KO mouse model with defined metabolic phenotypes, multiple orthogonal functional assays","pmids":["37544897"],"is_preprint":false},{"year":2024,"finding":"IFI27 co-immunoprecipitates with MDA5, with this interaction likely mediated by RNAs. IFI27 inhibits MDA5 oligomerization and activation, counteracting innate immune responses after SARS-CoV-2 infection or poly(I:C) transfection. IFI27 competes with MDA5 for poly(I:C) binding, providing a mechanism for its inhibition of MDA5 activation.","method":"Co-immunoprecipitation of IFI27 with MDA5; IFI27 overexpression, knockout, and knockdown cells; MDA5 oligomerization assay; poly(I:C) binding competition assay; SARS-CoV-2 infection model","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, competition binding assay, KO/KD/OE systems, single lab, multiple orthogonal methods","pmids":["39431052"],"is_preprint":false},{"year":2024,"finding":"IFI27 inhibits HIV-1 replication by degrading viral Gag proteins (p24 and p55) via the ubiquitin-proteasome pathway. The NPM-IFI27-37-115 domain interacts with the p24-N domain; the NPM-IFI27-76-122 domain is associated with K48 ubiquitin recruitment. SKP2 is identified as the probable E3 ubiquitin ligase mediating IFI27-induced p24/p55 ubiquitination and degradation. Human IFI27 shows a similar mechanism.","method":"Co-immunoprecipitation of IFI27 with p24/p55; ubiquitin-proteasome pathway assay; domain mapping; SKP2 identification as E3 ligase; IFI27 overexpression and knockdown; HIV-1 replication assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — Co-IP with defined domains, ubiquitin assay, E3 ligase identification, KD/OE with antiviral readout, single lab with multiple orthogonal methods","pmids":["39475279"],"is_preprint":false},{"year":2025,"finding":"IFI27 suppresses HBV transcription by promoting ubiquitination-dependent proteasomal degradation of C/EBPα (a cellular transcription factor critical for HBV RNA transcription) in the cytoplasm. The E3 ubiquitin ligase SKP2 mediates IFI27-induced C/EBPα ubiquitination and degradation; SKP2 knockdown abrogates IFI27's antiviral activity. IFI27 is predominantly localized in the cytoplasm. IFI27 knockdown diminishes IFN-alpha antiviral effect on HBV.","method":"IFI27 overexpression and knockdown in HBV-transfected and -infected cells (HepG2-NTCP, primary human hepatocytes); ubiquitination assay; SKP2 knockdown rescue experiment; HBV RNA transcription assay; RNA-seq; subcellular localization","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ubiquitination assay, E3 ligase rescue, KD/OE with mechanistic readout, multiple cell systems, single lab","pmids":["41081508"],"is_preprint":false},{"year":2025,"finding":"IFI27 interacts with PACT (PRKRA) and with PKR, where the IFI27-PACT interaction is likely mediated by dsRNAs or RNAs containing duplex regions, and the IFI27-PKR interaction is PACT-dependent. IFI27 potentiates PKR activity, leading to decreased protein translation, increased eIF2alpha phosphorylation, and increased stress granule formation. This function is demonstrated in cells infected with SARS-CoV-2, VSV, and after poly(I:C) transfection.","method":"Co-immunoprecipitation of IFI27 with PACT and PKR; IFI27 knockdown, knockout, and overexpression cells; eIF2alpha phosphorylation assay; stress granule imaging; protein translation assay; viral infection (SARS-CoV-2, VSV)","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing PACT-dependent PKR interaction, KD/KO/OE with defined molecular phenotypes, multiple viral systems, single lab","pmids":["40522981"],"is_preprint":false},{"year":2022,"finding":"USP18 deubiquitinates IFI27 and prevents its degradation (demonstrated by Co-IP). HOXA5 is a transcription factor that activates USP18 transcription by binding to its promoter (validated by ChIP and dual-luciferase assay), thereby stabilizing IFI27 and promoting ESCC cell malignant progression and cisplatin resistance.","method":"Co-immunoprecipitation of USP18 with IFI27; ChIP and dual-luciferase assay for HOXA5 binding USP18 promoter; IFI27 knockdown; ubiquitination/deubiquitination assays; cell viability, proliferation, apoptosis, invasion assays","journal":"Thoracic cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, luciferase reporter, KD with functional phenotype, single lab","pmids":["39993992"],"is_preprint":false},{"year":2025,"finding":"METTL3-mediated m6A methylation of IFI27 mRNA stabilizes the transcript; the m6A reader IGF2BP2 also affects IFI27 mRNA m6A methylation and expression. METTL3 depletion reduces IFI27 expression; IFI27 re-expression rescues the effects of METTL3 deficiency on ESCC cell behaviors.","method":"Methylated RNA immunoprecipitation (MeRIP); RIP assay; mRNA stability analysis; METTL3 and IGF2BP2 knockdown; IFI27 re-expression rescue; xenograft assay","journal":"Journal of biochemical and molecular toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP, RIP, mRNA stability assay with functional rescue, single lab","pmids":["39987518"],"is_preprint":false},{"year":2022,"finding":"miR-942-5p suppresses IFI27 translation by targeting the 3'-UTR of the IFI27 gene. IFI27 overexpression increases apoptosis and decreases Cryptosporidium parvum burden in HCT-8 cells via TRAIL and caspase-8 pathway. C. parvum induces downregulation of IFI27 via upregulation of miR-942-5p.","method":"3'-UTR reporter assay; miR-942-5p overexpression/suppression; IFI27 overexpression/knockdown; flow cytometry (apoptosis); Western blot of TRAIL and caspase-8; C. parvum burden quantification","journal":"Parasites & vectors","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'-UTR targeting validated, KD/OE with defined apoptotic pathway readout, single lab","pmids":["35974384"],"is_preprint":false},{"year":2024,"finding":"ADAMTS16 upregulates IFI27 protein through the NF-κB pathway, with a binding site between the NF-κB subunit P65 and the IFI27 promoter identified by dual-luciferase reporter assay. IFI27 knockdown reverses the promoting effects of ADAMTS16 on gastric cancer cell invasion, migration, and proliferation.","method":"Co-immunoprecipitation; immunofluorescence; western blot; dual-luciferase reporter assay for P65-IFI27 promoter binding; IFI27 knockdown rescue; in vitro and in vivo functional assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual-luciferase reporter for direct promoter binding, KD rescue experiment, single lab","pmids":["36232317"],"is_preprint":false},{"year":2024,"finding":"In situ single-cell spatial transcriptomics identified M1 macrophages as having elevated IFI27 expression in areas of SARS-CoV-2 infection, providing direct cell-type-level localization of IFI27 expression during infection.","method":"In situ single-cell resolved spatial transcriptomics during SARS-CoV-2 infection","journal":"EBioMedicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization finding in a spatial transcriptomics study, no functional follow-up","pmids":["38377798"],"is_preprint":false}],"current_model":"IFI27/ISG12 is an interferon-alpha-stimulated small hydrophobic protein that localizes primarily to mitochondria (and in some contexts the cytoplasm or nuclear envelope), where it promotes apoptosis via BH3-like domain interactions with Bcl-2 and mitochondrial membrane destabilization, sustains mitochondrial metabolic function by physically linking SDHB to the chaperone TRAP1 and activating HADHA in fatty acid oxidation, and modulates innate immune signaling by interacting with and suppressing the antiviral pattern recognition receptors RIG-I and MDA5, as well as potentiating PKR activation through PACT; additionally, IFI27 exerts antiviral activity against HBV by promoting SKP2-dependent ubiquitin-proteasomal degradation of the transcription factor C/EBPα, and against HIV-1 by targeting viral Gag proteins for K48-ubiquitin-mediated proteasomal degradation; its transcription is directly repressed by ATF3 (via promoter binding) and its mRNA stability is regulated by PABPC1/eIF4G competition with RNA exosomes and by METTL3-mediated m6A methylation read by IGF2BP2, while its protein stability is controlled by USP18-mediated deubiquitination."},"narrative":{"mechanistic_narrative":"IFI27 (ISG12) is a small interferon-stimulated hydrophobic protein that integrates mitochondrial metabolism, apoptosis, and antiviral innate immunity, acting as a context-dependent regulator of cell fate and host defense [PMID:27673746, PMID:37544897, PMID:37187533]. At mitochondria, full-length ISG12A sensitizes cells to apoptotic stimuli and directly induces apoptosis through two BH3-like motifs, co-immunoprecipitating with Bcl-2 and forming homodimers consistent with membrane pore formation [PMID:27673746]. In a non-apoptotic role at the same organelle, IFI27 sustains mitochondrial function: it physically binds SDHB and links it to the chaperone TRAP1 to protect succinate dehydrogenase from degradation, and binds and activates HADHA to drive fatty acid β-oxidation, supporting cristae morphogenesis and adaptive thermogenesis in brown adipocytes [PMID:37544897, PMID:29730295]. In innate immunity IFI27 acts as a negative regulator of cytoplasmic RNA sensing, binding nucleic acids and interacting with RIG-I and MDA5 to impair their activation—competing with MDA5 for poly(I:C) and blocking its oligomerization—while conversely potentiating PKR through a PACT-dependent interaction to increase eIF2α phosphorylation and stress granule formation [PMID:37187533, PMID:39431052, PMID:40522981]. IFI27 also exerts direct antiviral activity by routing viral and host proteins to the proteasome: it promotes SKP2-dependent ubiquitination and degradation of HIV-1 Gag (p24/p55) and of the HBV-supporting transcription factor C/EBPα [PMID:39475279, PMID:41081508]. As an interferon target, IFI27 expression is transcriptionally repressed by ATF3 binding its promoter and its protein is stabilized by USP18-mediated deubiquitination, coupling it to interferon and tumor-associated signaling [PMID:33539340, PMID:39993992]. Reported localization spans the nuclear envelope, mitochondria, and cytoplasm across cell contexts [PMID:11722583, PMID:27673746, PMID:41081508].","teleology":[{"year":2001,"claim":"Established the first subcellular address for the interferon-induced ISG12/IFI27 protein, anchoring it to the nuclear envelope.","evidence":"Subcellular fractionation of recombinant tagged protein and immunocytochemistry in IFN-alpha-treated HeLa cells","pmids":["11722583"],"confidence":"Medium","gaps":["Does not assign molecular function","Later work places IFI27 at mitochondria and cytoplasm, leaving localization context-dependent and unresolved"]},{"year":2013,"claim":"Linked IFI27 to innate immune regulation by showing it drives nuclear export of nuclear receptors to limit their anti-inflammatory activity, with genetic epistasis placing it upstream of NR4A1.","evidence":"ISG12-knockout mice in sepsis/endotoxemia models, macrophage assays, and NR4A1 double-knockout rescue","pmids":["23747037"],"confidence":"Medium","gaps":["Direct interaction interface with nuclear receptors not mapped","Mechanism connecting NR export to IL-6 not detailed"]},{"year":2015,"claim":"Defined a cell-cycle/proliferation role, showing IFI27 loss imposes S-phase arrest via CDK1 inhibition and p53/p21 activation, and that EGF stabilizes IFI27 protein.","evidence":"siRNA/overexpression in keratinocytes with flow cytometry, cyclin A/CDK1 Co-IP, and an imiquimod psoriasis mouse model","pmids":["25664647"],"confidence":"Medium","gaps":["Direct molecular target of IFI27 in the cell cycle not identified","Mechanism of EGF-mediated stabilization unknown"]},{"year":2016,"claim":"Provided the strongest mechanistic case for a pro-apoptotic mitochondrial function, identifying BH3-like motifs and Bcl-2 binding.","evidence":"Overexpression in HEK293, BH3 mutagenesis, Bcl-2 Co-IP, and mitochondrial fractionation/imaging","pmids":["27673746"],"confidence":"High","gaps":["Homodimer pore-formation model not structurally confirmed","How apoptotic and metabolic mitochondrial roles are partitioned is unclear"]},{"year":2018,"claim":"Revealed a metabolic mitochondrial function, showing IFI27 supports TCA/ETC gene expression and is required for adrenergic browning of white fat.","evidence":"Mitochondrial imaging/fractionation, siRNA/overexpression in brown adipocytes, and in vivo beta3-agonist treatment","pmids":["29730295"],"confidence":"Medium","gaps":["Molecular mechanism linking IFI27 to mitochondrial gene programs not yet defined here","Direct partners not identified at this stage"]},{"year":2020,"claim":"Generalized the nuclear-export function to estrogen receptor alpha, showing IFI27 bridges ERalpha to CRM1/XPO1 to attenuate ERalpha transactivation.","evidence":"Reciprocal Co-IP of IFI27 with ERalpha and CRM1/XPO1, reporter assays, and proliferation/migration assays in MCF-7 cells","pmids":["33117284"],"confidence":"Medium","gaps":["Direct binding interface not mapped","Whether export is direct cargo adaptation or indirect is unresolved"]},{"year":2021,"claim":"Identified direct transcriptional control of IFI27, with ATF3 binding its promoter to repress expression and restrain tumor cell growth.","evidence":"ChIP, RNA-seq, ATF3 gain/loss in TSCC lines, IFI27 knockdown, and in vivo rescue","pmids":["33539340"],"confidence":"High","gaps":["Upstream signals controlling ATF3 occupancy not defined","Downstream IFI27 effectors in TSCC not mapped"]},{"year":2022,"claim":"Established post-transcriptional and post-translational stabilization layers controlling IFI27 abundance via mRNA stability, m6A, miRNA, and deubiquitination.","evidence":"PABPC1/eIF4G Co-IP and mRNA stability assays (ESCC); USP18 Co-IP/deubiquitination with HOXA5 ChIP; miR-942-5p 3'-UTR reporter assays","pmids":["35346324","39993992","35974384"],"confidence":"Medium","gaps":["Relative contribution of each regulatory layer in vivo unknown","How these inputs are integrated under interferon signaling not resolved"]},{"year":2023,"claim":"Defined the dual mitochondrial-metabolic and antiviral-sensing functions: IFI27 protects SDHB via TRAP1 and activates HADHA, while binding RIG-I to suppress cytoplasmic RNA sensing.","evidence":"Interaction mapping and Co-IP with SDHB/HADHA/TRAP1 plus Ifi27-knockout metabolic phenotyping; RIG-I Co-IP with KD/OE in IAV/SARS-CoV-2/SeV infection","pmids":["37544897","37187533"],"confidence":"High","gaps":["Structural basis of SDHB-TRAP1 bridging not solved","Whether RIG-I suppression is purely RNA-mediated not fully resolved"]},{"year":2024,"claim":"Extended antiviral mechanisms: IFI27 blocks MDA5 oligomerization by competing for dsRNA and targets HIV-1 Gag for SKP2/K48-ubiquitin proteasomal degradation via mapped domains.","evidence":"MDA5 Co-IP and poly(I:C) competition assays; Gag (p24/p55) Co-IP, domain mapping, SKP2 identification, and ubiquitin-proteasome/HIV replication assays","pmids":["39431052","39475279"],"confidence":"High","gaps":["Reconciling immune-suppressive (RIG-I/MDA5) and antiviral (Gag degradation) roles mechanistically","Selectivity of SKP2 recruitment by IFI27 unexplained"]},{"year":2025,"claim":"Completed the antiviral/immune picture with SKP2-dependent C/EBPalpha degradation restricting HBV and PACT-dependent PKR potentiation enhancing translational stress responses.","evidence":"HBV ubiquitination/SKP2-rescue assays in HepG2-NTCP and hepatocytes; PACT/PKR Co-IP with eIF2alpha phosphorylation and stress-granule readouts in SARS-CoV-2/VSV models","pmids":["41081508","40522981"],"confidence":"High","gaps":["How IFI27 selects SKP2 substrates (Gag vs C/EBPalpha) is unknown","Net effect on interferon signaling of simultaneous PRR suppression and PKR activation unresolved"]},{"year":null,"claim":"It remains unknown how a single small protein coordinates its opposing roles—pro-apoptotic versus metabolism-sustaining at mitochondria, and PRR-suppressive versus PKR-activating in immunity—and what structural features dictate which function dominates in a given cell type.","evidence":"No experimental resolution of functional partitioning in the available corpus","pmids":[],"confidence":"Low","gaps":["No structural model of IFI27 or its complexes","No unifying framework for context-dependent function selection","Localization determinants (nuclear envelope vs mitochondria vs cytoplasm) not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8,10,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,10,9,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,4,9]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,10,13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11,12]}],"complexes":[],"partners":["RIG-I","MDA5","SDHB","HADHA","TRAP1","PRKRA","BCL-2","XPO1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P40305","full_name":"Interferon alpha-inducible protein 27, mitochondrial","aliases":["Interferon alpha-induced 11.5 kDa protein","Interferon-stimulated gene 12a protein","ISG12(a)","ISG12A"],"length_aa":122,"mass_kda":11.5,"function":"Probable adapter protein involved in different biological processes (PubMed:22427340, PubMed:27194766). Part of the signaling pathways that lead to apoptosis (PubMed:18330707, PubMed:24970806, PubMed:27673746). Involved in type-I interferon-induced apoptosis characterized by a rapid and robust release of cytochrome C from the mitochondria and activation of BAX and caspases 2, 3, 6, 8 and 9 (PubMed:18330707, PubMed:27673746). Also functions in TNFSF10-induced apoptosis (PubMed:24970806). May also have a function in the nucleus, where it may be involved in the interferon-induced negative regulation of the transcriptional activity of NR4A1, NR4A2 and NR4A3 through the enhancement of XPO1-mediated nuclear export of these nuclear receptors (PubMed:22427340). May thereby play a role in the vascular response to injury (By similarity). In the innate immune response, has an antiviral activity towards hepatitis C virus/HCV (PubMed:27194766, PubMed:27777077). May prevent the replication of the virus by recruiting both the hepatitis C virus non-structural protein 5A/NS5A and the ubiquitination machinery via SKP2, promoting the ubiquitin-mediated proteasomal degradation of NS5A (PubMed:27194766, PubMed:27777077). Also promotes virus-induced pyroptosis by activating CASP3 in the mitochondria after 'Lys-6'-linked ubiquitination by TRIM21 (PubMed:36426955)","subcellular_location":"Mitochondrion membrane; Nucleus inner membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P40305/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFI27","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IFI27","total_profiled":1310},"omim":[{"mim_id":"618886","title":"PSEUDO-TORCH SYNDROME 3; PTORCH3","url":"https://www.omim.org/entry/618886"},{"mim_id":"611320","title":"INTERFERON-ALPHA-INDUCIBLE PROTEIN 27-LIKE 1; IFI27L1","url":"https://www.omim.org/entry/611320"},{"mim_id":"611319","title":"INTERFERON-ALPHA-INDUCIBLE PROTEIN 27-LIKE 2; IFI27L2","url":"https://www.omim.org/entry/611319"},{"mim_id":"603263","title":"CARBONIC ANHYDRASE XII; CA12","url":"https://www.omim.org/entry/603263"},{"mim_id":"603254","title":"SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY A, MEMBER 4; SMARCA4","url":"https://www.omim.org/entry/603254"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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novel immune biomarker IFI27 discriminates between influenza and bacteria in patients with suspected respiratory infection.","date":"2017","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/28619954","citation_count":106,"is_preprint":false},{"pmid":"20939681","id":"PMC_20939681","title":"Emerging roles of FAM14 family members (G1P3/ISG 6-16 and ISG12/IFI27) in innate immunity and cancer.","date":"2010","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/20939681","citation_count":105,"is_preprint":false},{"pmid":"15086558","id":"PMC_15086558","title":"Interferon alpha-inducible protein 27 (IFI27) is upregulated in psoriatic skin and certain epithelial cancers.","date":"2004","source":"The Journal of investigative 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localizes to the nuclear envelope (nuclear membrane), as demonstrated by baculovirus-expressed and FLAG-tagged recombinant ISG12 sedimentation in nuclear envelope fractions and immunocytochemical detection in IFN-alpha-treated HeLa cells.\",\n      \"method\": \"Subcellular fractionation of baculovirus-expressed and FLAG-tagged recombinant protein in HEK293 cells; immunocytochemistry in HeLa cells treated with IFN-alpha\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with two orthogonal methods (fractionation + immunocytochemistry), single lab\",\n      \"pmids\": [\"11722583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ISG12 (IFI27) directly interacts with nuclear receptors (NRs) and acts as a co-factor stimulating nuclear export of NRs, thereby reducing the anti-inflammatory potential of NRs such as NR4A1. ISG12-deficient mice showed prolonged survival and reduced IL-6 levels in experimental sepsis, and this phenotype was restored in ISG12/NR4A1 double-deficient mice, placing ISG12 upstream of NR4A1 in innate immune regulation.\",\n      \"method\": \"ISG12-knockout mice in cecal ligation and puncture (CLP) and endotoxemia models; in vitro peritoneal macrophage experiments; genetic epistasis with NR4A1 double-knockout mice; direct interaction assay with NRs\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with double-knockout rescue, in vivo and in vitro experiments, single lab\",\n      \"pmids\": [\"23747037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IFI27 knockdown in keratinocytes reduces proliferation and causes S-phase arrest associated with increased Tyr15 phosphorylation of CDK1, reduced CDC25B, reduced formation of cyclin A/CDK1 complex (demonstrated by co-immunoprecipitation), and activation of p53 (Ser15 phosphorylation) with increased p21 expression. EGF stabilizes IFI27 protein by prolonging its half-life.\",\n      \"method\": \"siRNA knockdown and overexpression in keratinocytes; MTT assay; flow cytometry; co-immunoprecipitation of cyclin A/CDK1; Western blot; in vivo topical siRNA in imiquimod-induced psoriasis mouse model\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KD/KO with defined cellular and molecular phenotypes, in vivo validation, single lab\",\n      \"pmids\": [\"25664647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Full-length ISG12A/IFI27 protein sensitizes cells to TNF-alpha- and gossypol-induced apoptosis; shorter ISG12A variants directly induce apoptosis in HEK293 cells. ISG12A co-immunoprecipitates with Bcl-2, and apoptotic effects are reduced in Bcl-2-expressing cells. Two putative BH3-like motifs in the ISG12 motif are implicated. Full-length ISG12A forms homodimers suggesting a role in pore formation. ISG12A, its variants, and ISG12B localize to mitochondria.\",\n      \"method\": \"Overexpression in HEK293 cells; BH3 mutagenesis; co-immunoprecipitation with Bcl-2; mitochondrial localization by subcellular fractionation/imaging; apoptosis assays in Bcl-2-expressing cells\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — Co-IP, site-directed mutagenesis of BH3 motifs, subcellular fractionation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"27673746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ifi27 protein localizes to mitochondria in adipocytes. Knockdown of Ifi27 reduces expression of TCA cycle key enzymes, electron transport chain subunits, and Ucp1 in brown and beige adipocytes, and blocks beta3-adrenergic agonist-induced browning of subcutaneous white fat. Ifi27 expression is induced by beta3-adrenergic activation in adipose tissue.\",\n      \"method\": \"Mitochondrial localization by imaging/fractionation; siRNA knockdown; overexpression in brown adipocytes; in vivo beta3-adrenergic agonist treatment; RT-qPCR and Western blot for TCA/ETC/Ucp1 markers\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization, KD and OE with defined molecular phenotypes, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29730295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IFI27/ISG12 interacts with estrogen receptor alpha (ERα) and facilitates the interaction between ERα and CRM1/XPO1, promoting nuclear export of ERα to the cytoplasm, thereby attenuating ERα transactivation activity and expression of ERα-dependent genes. IFI27 overexpression reduces MCF-7 cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation of IFI27 with ERα and CRM1/XPO1; overexpression in MCF-7 breast cancer cells; reporter assay for ERα transactivation; 2D/3D proliferation assays; wound-healing migration assay\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional overexpression assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33117284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATF3 transcription factor binds the promoter regions of IFI27 (and IFI6) as shown by ChIP assay, and negatively regulates IFI27 expression. Loss of ATF3 upregulates IFI27 and promotes TSCC cell growth and migration; IFI27 knockdown blocks the growth/migration induced by ATF3 deletion, and IFI27 overexpression counteracts ATF3 overexpression-mediated inhibition.\",\n      \"method\": \"ChIP assay; RNA-seq; gain- and loss-of-function of ATF3 in four TSCC cell lines; siRNA knockdown of IFI27; in vivo mouse model\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP showing direct promoter binding, multiple cell lines, in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"33539340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PABPC1 interacts with eIF4G to increase the stability of IFI27 mRNA by competing with RNA exosomes, activating the IFN/IFI27 signaling pathway to enhance ESCC cell proliferation and invasion.\",\n      \"method\": \"Co-immunoprecipitation of PABPC1 with eIF4G; mRNA stability assays; PABPC1 overexpression/knockdown in ESCC cells; in vitro and in vivo proliferation/invasion assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mRNA stability assay, functional KD/OE, single lab\",\n      \"pmids\": [\"35346324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFI27 counteracts innate immune responses triggered by cytoplasmic RNA recognition after influenza A virus, SARS-CoV-2, Sendai virus infections, and dsRNA transfection. IFI27 interacts with nucleic acids and with RIG-I (most likely RNA-mediated), and this interaction impairs RIG-I activation. IFI27 has a positive effect on IAV and SARS-CoV-2 replication in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation of IFI27 with RIG-I; IFI27 knockdown and overexpression cells; viral infection models (IAV, SARS-CoV-2, SeV); dsRNA transfection; in vivo experiments; innate immune response assays\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with RIG-I, KD/OE with defined antiviral phenotype, multiple viral systems, single lab\",\n      \"pmids\": [\"37187533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFI27 is required for cristae morphogenesis and sustains succinate dehydrogenase (SDH) function and fatty acid oxidation in brown adipocytes. IFI27 physically binds SDHB and HADHA (identified by interaction mapping). IFI27 links SDHB to chaperone TRAP1, shielding SDHB from oxidative damage-triggered degradation. IFI27 also increases HADHA catalytic activity in beta-oxidation. Ifi27-knockout brown fat shows reduced SDH levels, impaired fatty acid oxidation, impaired oxygen consumption and defective thermogenesis.\",\n      \"method\": \"IFI27 protein interaction mapping; co-immunoprecipitation of IFI27 with SDHB, HADHA, TRAP1; Ifi27-knockout mice; oxygen consumption assay; beta-oxidation assay; cold challenge thermogenesis model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — physical interaction mapping, Co-IP, KO mouse model with defined metabolic phenotypes, multiple orthogonal functional assays\",\n      \"pmids\": [\"37544897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFI27 co-immunoprecipitates with MDA5, with this interaction likely mediated by RNAs. IFI27 inhibits MDA5 oligomerization and activation, counteracting innate immune responses after SARS-CoV-2 infection or poly(I:C) transfection. IFI27 competes with MDA5 for poly(I:C) binding, providing a mechanism for its inhibition of MDA5 activation.\",\n      \"method\": \"Co-immunoprecipitation of IFI27 with MDA5; IFI27 overexpression, knockout, and knockdown cells; MDA5 oligomerization assay; poly(I:C) binding competition assay; SARS-CoV-2 infection model\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, competition binding assay, KO/KD/OE systems, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39431052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFI27 inhibits HIV-1 replication by degrading viral Gag proteins (p24 and p55) via the ubiquitin-proteasome pathway. The NPM-IFI27-37-115 domain interacts with the p24-N domain; the NPM-IFI27-76-122 domain is associated with K48 ubiquitin recruitment. SKP2 is identified as the probable E3 ubiquitin ligase mediating IFI27-induced p24/p55 ubiquitination and degradation. Human IFI27 shows a similar mechanism.\",\n      \"method\": \"Co-immunoprecipitation of IFI27 with p24/p55; ubiquitin-proteasome pathway assay; domain mapping; SKP2 identification as E3 ligase; IFI27 overexpression and knockdown; HIV-1 replication assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — Co-IP with defined domains, ubiquitin assay, E3 ligase identification, KD/OE with antiviral readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39475279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFI27 suppresses HBV transcription by promoting ubiquitination-dependent proteasomal degradation of C/EBPα (a cellular transcription factor critical for HBV RNA transcription) in the cytoplasm. The E3 ubiquitin ligase SKP2 mediates IFI27-induced C/EBPα ubiquitination and degradation; SKP2 knockdown abrogates IFI27's antiviral activity. IFI27 is predominantly localized in the cytoplasm. IFI27 knockdown diminishes IFN-alpha antiviral effect on HBV.\",\n      \"method\": \"IFI27 overexpression and knockdown in HBV-transfected and -infected cells (HepG2-NTCP, primary human hepatocytes); ubiquitination assay; SKP2 knockdown rescue experiment; HBV RNA transcription assay; RNA-seq; subcellular localization\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ubiquitination assay, E3 ligase rescue, KD/OE with mechanistic readout, multiple cell systems, single lab\",\n      \"pmids\": [\"41081508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFI27 interacts with PACT (PRKRA) and with PKR, where the IFI27-PACT interaction is likely mediated by dsRNAs or RNAs containing duplex regions, and the IFI27-PKR interaction is PACT-dependent. IFI27 potentiates PKR activity, leading to decreased protein translation, increased eIF2alpha phosphorylation, and increased stress granule formation. This function is demonstrated in cells infected with SARS-CoV-2, VSV, and after poly(I:C) transfection.\",\n      \"method\": \"Co-immunoprecipitation of IFI27 with PACT and PKR; IFI27 knockdown, knockout, and overexpression cells; eIF2alpha phosphorylation assay; stress granule imaging; protein translation assay; viral infection (SARS-CoV-2, VSV)\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing PACT-dependent PKR interaction, KD/KO/OE with defined molecular phenotypes, multiple viral systems, single lab\",\n      \"pmids\": [\"40522981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP18 deubiquitinates IFI27 and prevents its degradation (demonstrated by Co-IP). HOXA5 is a transcription factor that activates USP18 transcription by binding to its promoter (validated by ChIP and dual-luciferase assay), thereby stabilizing IFI27 and promoting ESCC cell malignant progression and cisplatin resistance.\",\n      \"method\": \"Co-immunoprecipitation of USP18 with IFI27; ChIP and dual-luciferase assay for HOXA5 binding USP18 promoter; IFI27 knockdown; ubiquitination/deubiquitination assays; cell viability, proliferation, apoptosis, invasion assays\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, luciferase reporter, KD with functional phenotype, single lab\",\n      \"pmids\": [\"39993992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3-mediated m6A methylation of IFI27 mRNA stabilizes the transcript; the m6A reader IGF2BP2 also affects IFI27 mRNA m6A methylation and expression. METTL3 depletion reduces IFI27 expression; IFI27 re-expression rescues the effects of METTL3 deficiency on ESCC cell behaviors.\",\n      \"method\": \"Methylated RNA immunoprecipitation (MeRIP); RIP assay; mRNA stability analysis; METTL3 and IGF2BP2 knockdown; IFI27 re-expression rescue; xenograft assay\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP, RIP, mRNA stability assay with functional rescue, single lab\",\n      \"pmids\": [\"39987518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-942-5p suppresses IFI27 translation by targeting the 3'-UTR of the IFI27 gene. IFI27 overexpression increases apoptosis and decreases Cryptosporidium parvum burden in HCT-8 cells via TRAIL and caspase-8 pathway. C. parvum induces downregulation of IFI27 via upregulation of miR-942-5p.\",\n      \"method\": \"3'-UTR reporter assay; miR-942-5p overexpression/suppression; IFI27 overexpression/knockdown; flow cytometry (apoptosis); Western blot of TRAIL and caspase-8; C. parvum burden quantification\",\n      \"journal\": \"Parasites & vectors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'-UTR targeting validated, KD/OE with defined apoptotic pathway readout, single lab\",\n      \"pmids\": [\"35974384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ADAMTS16 upregulates IFI27 protein through the NF-κB pathway, with a binding site between the NF-κB subunit P65 and the IFI27 promoter identified by dual-luciferase reporter assay. IFI27 knockdown reverses the promoting effects of ADAMTS16 on gastric cancer cell invasion, migration, and proliferation.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence; western blot; dual-luciferase reporter assay for P65-IFI27 promoter binding; IFI27 knockdown rescue; in vitro and in vivo functional assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual-luciferase reporter for direct promoter binding, KD rescue experiment, single lab\",\n      \"pmids\": [\"36232317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In situ single-cell spatial transcriptomics identified M1 macrophages as having elevated IFI27 expression in areas of SARS-CoV-2 infection, providing direct cell-type-level localization of IFI27 expression during infection.\",\n      \"method\": \"In situ single-cell resolved spatial transcriptomics during SARS-CoV-2 infection\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization finding in a spatial transcriptomics study, no functional follow-up\",\n      \"pmids\": [\"38377798\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFI27/ISG12 is an interferon-alpha-stimulated small hydrophobic protein that localizes primarily to mitochondria (and in some contexts the cytoplasm or nuclear envelope), where it promotes apoptosis via BH3-like domain interactions with Bcl-2 and mitochondrial membrane destabilization, sustains mitochondrial metabolic function by physically linking SDHB to the chaperone TRAP1 and activating HADHA in fatty acid oxidation, and modulates innate immune signaling by interacting with and suppressing the antiviral pattern recognition receptors RIG-I and MDA5, as well as potentiating PKR activation through PACT; additionally, IFI27 exerts antiviral activity against HBV by promoting SKP2-dependent ubiquitin-proteasomal degradation of the transcription factor C/EBPα, and against HIV-1 by targeting viral Gag proteins for K48-ubiquitin-mediated proteasomal degradation; its transcription is directly repressed by ATF3 (via promoter binding) and its mRNA stability is regulated by PABPC1/eIF4G competition with RNA exosomes and by METTL3-mediated m6A methylation read by IGF2BP2, while its protein stability is controlled by USP18-mediated deubiquitination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IFI27 (ISG12) is a small interferon-stimulated hydrophobic protein that integrates mitochondrial metabolism, apoptosis, and antiviral innate immunity, acting as a context-dependent regulator of cell fate and host defense [#3, #9, #8]. At mitochondria, full-length ISG12A sensitizes cells to apoptotic stimuli and directly induces apoptosis through two BH3-like motifs, co-immunoprecipitating with Bcl-2 and forming homodimers consistent with membrane pore formation [#3]. In a non-apoptotic role at the same organelle, IFI27 sustains mitochondrial function: it physically binds SDHB and links it to the chaperone TRAP1 to protect succinate dehydrogenase from degradation, and binds and activates HADHA to drive fatty acid β-oxidation, supporting cristae morphogenesis and adaptive thermogenesis in brown adipocytes [#9, #4]. In innate immunity IFI27 acts as a negative regulator of cytoplasmic RNA sensing, binding nucleic acids and interacting with RIG-I and MDA5 to impair their activation—competing with MDA5 for poly(I:C) and blocking its oligomerization—while conversely potentiating PKR through a PACT-dependent interaction to increase eIF2α phosphorylation and stress granule formation [#8, #10, #13]. IFI27 also exerts direct antiviral activity by routing viral and host proteins to the proteasome: it promotes SKP2-dependent ubiquitination and degradation of HIV-1 Gag (p24/p55) and of the HBV-supporting transcription factor C/EBPα [#11, #12]. As an interferon target, IFI27 expression is transcriptionally repressed by ATF3 binding its promoter and its protein is stabilized by USP18-mediated deubiquitination, coupling it to interferon and tumor-associated signaling [#6, #14]. Reported localization spans the nuclear envelope, mitochondria, and cytoplasm across cell contexts [#0, #3, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the first subcellular address for the interferon-induced ISG12/IFI27 protein, anchoring it to the nuclear envelope.\",\n      \"evidence\": \"Subcellular fractionation of recombinant tagged protein and immunocytochemistry in IFN-alpha-treated HeLa cells\",\n      \"pmids\": [\"11722583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not assign molecular function\", \"Later work places IFI27 at mitochondria and cytoplasm, leaving localization context-dependent and unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked IFI27 to innate immune regulation by showing it drives nuclear export of nuclear receptors to limit their anti-inflammatory activity, with genetic epistasis placing it upstream of NR4A1.\",\n      \"evidence\": \"ISG12-knockout mice in sepsis/endotoxemia models, macrophage assays, and NR4A1 double-knockout rescue\",\n      \"pmids\": [\"23747037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction interface with nuclear receptors not mapped\", \"Mechanism connecting NR export to IL-6 not detailed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a cell-cycle/proliferation role, showing IFI27 loss imposes S-phase arrest via CDK1 inhibition and p53/p21 activation, and that EGF stabilizes IFI27 protein.\",\n      \"evidence\": \"siRNA/overexpression in keratinocytes with flow cytometry, cyclin A/CDK1 Co-IP, and an imiquimod psoriasis mouse model\",\n      \"pmids\": [\"25664647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target of IFI27 in the cell cycle not identified\", \"Mechanism of EGF-mediated stabilization unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the strongest mechanistic case for a pro-apoptotic mitochondrial function, identifying BH3-like motifs and Bcl-2 binding.\",\n      \"evidence\": \"Overexpression in HEK293, BH3 mutagenesis, Bcl-2 Co-IP, and mitochondrial fractionation/imaging\",\n      \"pmids\": [\"27673746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Homodimer pore-formation model not structurally confirmed\", \"How apoptotic and metabolic mitochondrial roles are partitioned is unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a metabolic mitochondrial function, showing IFI27 supports TCA/ETC gene expression and is required for adrenergic browning of white fat.\",\n      \"evidence\": \"Mitochondrial imaging/fractionation, siRNA/overexpression in brown adipocytes, and in vivo beta3-agonist treatment\",\n      \"pmids\": [\"29730295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking IFI27 to mitochondrial gene programs not yet defined here\", \"Direct partners not identified at this stage\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Generalized the nuclear-export function to estrogen receptor alpha, showing IFI27 bridges ERalpha to CRM1/XPO1 to attenuate ERalpha transactivation.\",\n      \"evidence\": \"Reciprocal Co-IP of IFI27 with ERalpha and CRM1/XPO1, reporter assays, and proliferation/migration assays in MCF-7 cells\",\n      \"pmids\": [\"33117284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface not mapped\", \"Whether export is direct cargo adaptation or indirect is unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified direct transcriptional control of IFI27, with ATF3 binding its promoter to repress expression and restrain tumor cell growth.\",\n      \"evidence\": \"ChIP, RNA-seq, ATF3 gain/loss in TSCC lines, IFI27 knockdown, and in vivo rescue\",\n      \"pmids\": [\"33539340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling ATF3 occupancy not defined\", \"Downstream IFI27 effectors in TSCC not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established post-transcriptional and post-translational stabilization layers controlling IFI27 abundance via mRNA stability, m6A, miRNA, and deubiquitination.\",\n      \"evidence\": \"PABPC1/eIF4G Co-IP and mRNA stability assays (ESCC); USP18 Co-IP/deubiquitination with HOXA5 ChIP; miR-942-5p 3'-UTR reporter assays\",\n      \"pmids\": [\"35346324\", \"39993992\", \"35974384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each regulatory layer in vivo unknown\", \"How these inputs are integrated under interferon signaling not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the dual mitochondrial-metabolic and antiviral-sensing functions: IFI27 protects SDHB via TRAP1 and activates HADHA, while binding RIG-I to suppress cytoplasmic RNA sensing.\",\n      \"evidence\": \"Interaction mapping and Co-IP with SDHB/HADHA/TRAP1 plus Ifi27-knockout metabolic phenotyping; RIG-I Co-IP with KD/OE in IAV/SARS-CoV-2/SeV infection\",\n      \"pmids\": [\"37544897\", \"37187533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SDHB-TRAP1 bridging not solved\", \"Whether RIG-I suppression is purely RNA-mediated not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended antiviral mechanisms: IFI27 blocks MDA5 oligomerization by competing for dsRNA and targets HIV-1 Gag for SKP2/K48-ubiquitin proteasomal degradation via mapped domains.\",\n      \"evidence\": \"MDA5 Co-IP and poly(I:C) competition assays; Gag (p24/p55) Co-IP, domain mapping, SKP2 identification, and ubiquitin-proteasome/HIV replication assays\",\n      \"pmids\": [\"39431052\", \"39475279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciling immune-suppressive (RIG-I/MDA5) and antiviral (Gag degradation) roles mechanistically\", \"Selectivity of SKP2 recruitment by IFI27 unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Completed the antiviral/immune picture with SKP2-dependent C/EBPalpha degradation restricting HBV and PACT-dependent PKR potentiation enhancing translational stress responses.\",\n      \"evidence\": \"HBV ubiquitination/SKP2-rescue assays in HepG2-NTCP and hepatocytes; PACT/PKR Co-IP with eIF2alpha phosphorylation and stress-granule readouts in SARS-CoV-2/VSV models\",\n      \"pmids\": [\"41081508\", \"40522981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IFI27 selects SKP2 substrates (Gag vs C/EBPalpha) is unknown\", \"Net effect on interferon signaling of simultaneous PRR suppression and PKR activation unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how a single small protein coordinates its opposing roles—pro-apoptotic versus metabolism-sustaining at mitochondria, and PRR-suppressive versus PKR-activating in immunity—and what structural features dictate which function dominates in a given cell type.\",\n      \"evidence\": \"No experimental resolution of functional partitioning in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of IFI27 or its complexes\", \"No unifying framework for context-dependent function selection\", \"Localization determinants (nuclear envelope vs mitochondria vs cytoplasm) not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8, 10, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 10, 9, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 4, 9]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 10, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RIG-I\", \"MDA5\", \"SDHB\", \"HADHA\", \"TRAP1\", \"PRKRA\", \"Bcl-2\", \"XPO1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}