IFIT3 (ISG60/RIG-G) is an interferon-stimulated gene encoding a TPR domain-containing protein that serves as a scaffold and regulatory component in innate antiviral immunity. IFIT3 functions primarily by forming heterocomplexes with IFIT1 and IFIT2: it stabilizes IFIT1 protein, enhances IFIT1's cap-0 RNA binding specificity, and negatively regulates IFIT2's pro-apoptotic function. The IFIT2-IFIT3 heterodimer specifically targets viral mRNAs with short 5' UTRs (<50 nucleotides). IFIT3 also amplifies interferon signaling through MAVS-TBK1 stabilization and STING pathway activation. The protein localizes to cytoplasm and mitochondria. Unlike IFIT2, which promotes apoptosis, IFIT3 negatively regulates apoptosis and has been implicated in tumor progression through PD-L1 upregulation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003723 RNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: IFIT3 contributes to RNA binding in the context of IFIT complexes. The IFIT2-IFIT3 heterodimer binds viral mRNAs with short 5' UTRs. Core function. Supporting Evidence: file:human/IFIT3/IFIT3-deep-research-perplexity.md The IFIT2-IFIT3 complex has been demonstrated to specifically target and inhibit translation of messenger RNAs with 5' untranslated regions shorter than approximately 50 nucleotides in length |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Cytosolic localization confirmed by multiple studies. Core localization. Supporting Evidence: file:human/IFIT3/IFIT3-deep-research-perplexity.md IFIT3 exhibits characteristically diffuse, total cytoplasmic localization in both uninfected cells expressing the protein exogenously and in cells treated with interferon-alpha |
| GO:0071345 cellular response to cytokine stimulus | IBA GO_REF:0000033 | ACCEPT | Summary: IFIT3 is an interferon-stimulated gene induced through JAK-STAT signaling in response to type I/III interferons. Supporting Evidence: file:human/IFIT3/IFIT3-deep-research-perplexity.md IFIT3 represents one of the most highly upregulated interferon-stimulated genes following viral infection or interferon exposure |
| GO:0140374 antiviral innate immune response | IBA GO_REF:0000033 | ACCEPT | Summary: Antiviral innate immune response is a core function. IFIT3 enhances antiviral activity by stabilizing IFIT1 and forming IFIT2-IFIT3 complexes that target viral RNA. Supporting Evidence: file:human/IFIT3/IFIT3-deep-research-perplexity.md IFIT3 functions as a critical amplification node within multiple interconnected signaling cascades that culminate in robust type I interferon production |
| GO:0002376 immune system process | IEA GO_REF:0000043 | ACCEPT | Summary: General immune process term. More specific terms preferred. Supporting Evidence: file:human/IFIT3/IFIT3-deep-research-perplexity.md Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3), also known as ISG60, CIG49, and RIG-G, represents a critical effector molecule in the innate immune response to viral infection |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasmic localization is well-supported. Supporting Evidence: PMID:18706081 IFIT4 protein was localized exclusively to the cytoplasm |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: Mitochondrial localization is supported by IFIT3's interaction with MAVS at mitochondria. Functional localization for signal amplification. Supporting Evidence: file:human/IFIT3/IFIT3-deep-research-perplexity.md IFIT3 has been demonstrated to stabilize MAVS interactions with the adaptor kinase TBK1 |
| GO:0045087 innate immune response | IEA GO_REF:0000043 | ACCEPT | Summary: IFIT3 is a key innate immune effector. Well-supported. Supporting Evidence: PMID:21813773 our study characterizes IFIT3 as an important modulator in innate immunity, revealing a new function of the IFIT family proteins |
| GO:0051607 defense response to virus | IEA GO_REF:0000120 | ACCEPT | Summary: Defense response to virus is a core function of IFIT3. Supporting Evidence: PMID:21642987 In the absence of IFIT1, the growth and pathogenicity of viruses containing PPP-RNA was much greater file:human/IFIT3/IFIT3-deep-research-perplexity.md host antiviral responses are significantly boosted or crippled in the presence or absence of IFIT3 |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | REMOVE | Summary: High-throughput interaction study. Generic protein binding uninformative. Reason: Generic protein binding per curation guidelines. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network. |
| GO:0005515 protein binding | IPI PMID:17050680 RIG-G as a key mediator of the antiproliferative activity of... | REMOVE | Summary: This paper shows IFIT3 (RIG-G) mediates antiproliferative effects through p21/p27. Generic protein binding annotation doesn't capture this function. Reason: Generic protein binding; functional annotation better captured elsewhere. Supporting Evidence: PMID:17050680 RIG-G as a key mediator of the antiproliferative activity of interferon-related pathways through enhancing p21 and p27 proteins. |
| GO:0005515 protein binding | IPI PMID:21163940 Interactome mapping suggests new mechanistic details underly... | REMOVE | Summary: Alzheimer's interactome study. Generic protein binding uninformative. Reason: Generic protein binding per curation guidelines. Supporting Evidence: PMID:21163940 Interactome mapping suggests new mechanistic details underlying Alzheimer's disease. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | REMOVE | Summary: Next-gen sequencing interactome study. Generic protein binding uninformative. Reason: High-throughput study; generic protein binding. Supporting Evidence: PMID:21516116 Next-generation sequencing to generate interactome datasets. |
| GO:0005515 protein binding | IPI PMID:21642987 IFIT1 is an antiviral protein that recognizes 5'-triphosphat... | REMOVE | Summary: This paper (IFIT1 recognizes 5'-triphosphate RNA) shows IFIT3 interacts with IFIT1 to enhance antiviral function. More specific than generic protein binding. Reason: Generic protein binding; IFIT1 interaction captured by complex function. Supporting Evidence: PMID:21642987 IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interactome mapping. Generic protein binding. Reason: High-throughput study; generic protein binding. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: Macromolecular interaction study. Generic protein binding. Reason: Generic protein binding per curation guidelines. Supporting Evidence: PMID:25910212 Widespread macromolecular interaction perturbations in human genetic disorders. |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | REMOVE | Summary: Barcode Fusion Genetics screen. Generic protein binding. Reason: High-throughput study; generic protein binding. Supporting Evidence: PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusion Genetics. |
| GO:0005515 protein binding | IPI PMID:27107014 An inter-species protein-protein interaction network across ... | REMOVE | Summary: Cross-species interactome study. Generic protein binding. Reason: High-throughput study; generic protein binding. Supporting Evidence: PMID:27107014 An inter-species protein-protein interaction network across vast evolutionary distance. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: BioPlex interactome study. Generic protein binding. Reason: High-throughput study; generic protein binding. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks. |
| GO:0005515 protein binding | IPI PMID:30833792 A protein-interaction network of interferon-stimulated genes... | REMOVE | Summary: ISG protein-protein interaction network study. Shows IFIT3 interactions within ISG network but annotation is too generic. Reason: Generic protein binding; ISG complex function captured elsewhere. Supporting Evidence: PMID:30833792 Mar 4. A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Population genetics protein interaction study. Generic protein binding. Reason: Generic protein binding per curation guidelines. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Human binary interactome reference map. Generic protein binding. Reason: High-throughput study; generic protein binding. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Cell-specific interactome remodeling study. Generic protein binding. Reason: High-throughput study; generic protein binding. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0042802 identical protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | ACCEPT | Summary: IFIT3 forms homodimers that can dissociate to form more stable heterodimers with IFIT2. This is functionally relevant for complex assembly. Supporting Evidence: file:human/IFIT3/IFIT3-deep-research-perplexity.md IFIT2 and IFIT3 homodimers can initially associate and then dissociate to form a more stable IFIT2-IFIT3 heterodimer PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network. |
| GO:0042802 identical protein binding | IPI PMID:21163940 Interactome mapping suggests new mechanistic details underly... | ACCEPT | Summary: Consistent with homodimer formation. IFIT3 forms homodimers. Supporting Evidence: PMID:21190939 ISG60 are able to form homomeric complexes PMID:21163940 Interactome mapping suggests new mechanistic details underlying Alzheimer's disease. |
| GO:0042802 identical protein binding | IPI PMID:21642987 IFIT1 is an antiviral protein that recognizes 5'-triphosphat... | ACCEPT | Summary: Consistent with homodimer formation documented in IFIT complex studies. Supporting Evidence: PMID:21642987 the antiviral protein IFIT1 (interferon-induced protein with tetratricopeptide repeats 1) mediated binding of a larger protein complex containing other IFIT family members |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based evidence for mitochondrial localization. Supporting Evidence: PMID:21813773 the tetratrico-peptide repeat motif (E164/E165) of IFIT3 interacts with the N terminus (K38) of TBK1, thus bridging TBK1 to MAVS on the mitochondrion |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based evidence for cytosolic localization. Supporting Evidence: file:human/IFIT3/IFIT3-deep-research-perplexity.md IFIT3 exhibits characteristically diffuse, total cytoplasmic localization in both uninfected cells expressing the protein exogenously and in cells treated with interferon-alpha |
| GO:0005737 cytoplasm | IDA PMID:17050680 RIG-G as a key mediator of the antiproliferative activity of... | ACCEPT | Summary: Direct experimental evidence for cytoplasmic localization. Supporting Evidence: PMID:17050680 The RIG-G gene, originally isolated from an acute promyelocytic leukemia cell line NB4, codes for a 60-kDa cytoplasmic protein |
| GO:0140374 antiviral innate immune response | IDA PMID:21642987 IFIT1 is an antiviral protein that recognizes 5'-triphosphat... | ACCEPT | Summary: Direct evidence from IFIT1 antiviral study showing IFIT3 enhances IFIT1-mediated antiviral response. Core function. Supporting Evidence: PMID:21642987 we propose that the IFIT complex antagonizes viruses by sequestering specific viral nucleic acids |
| GO:0005515 protein binding | IPI PMID:21190939 The interferon stimulated gene 54 promotes apoptosis. | REMOVE | Summary: This paper shows IFIT3 binds IFIT2 and negatively regulates IFIT2-mediated apoptosis. Generic term doesn't capture the functional significance. Reason: Generic protein binding; IFIT2 interaction function captured elsewhere. Supporting Evidence: PMID:21190939 2010 Dec 29. The interferon stimulated gene 54 promotes apoptosis. |
| GO:0005515 protein binding | IPI PMID:21813773 IFN-induced TPR protein IFIT3 potentiates antiviral signalin... | REMOVE | Summary: Key paper showing IFIT3 bridges MAVS and TBK1 for antiviral signaling. Generic protein binding doesn't capture this adaptor function. Reason: Generic protein binding; MAVS-TBK1 bridging function captured elsewhere. Supporting Evidence: PMID:21813773 Aug 3. IFN-induced TPR protein IFIT3 potentiates antiviral signaling by bridging MAVS and TBK1. |
| GO:0005737 cytoplasm | IDA PMID:18706081 Interferon-induced protein IFIT4 is associated with systemic... | ACCEPT | Summary: Direct evidence for cytoplasmic localization in SLE study. Supporting Evidence: PMID:18706081 IFIT4 protein was localized exclusively to the cytoplasm |
| GO:0005739 mitochondrion | IDA PMID:21813773 IFN-induced TPR protein IFIT3 potentiates antiviral signalin... | ACCEPT | Summary: Key paper showing IFIT3 localizes to mitochondria to bridge MAVS and TBK1. Functional mitochondrial localization for signaling. Supporting Evidence: PMID:21813773 IFN-induced TPR protein IFIT3 potentiates antiviral signaling by bridging MAVS and TBK1 |
| GO:0008285 negative regulation of cell population proliferation | IDA PMID:17050680 RIG-G as a key mediator of the antiproliferative activity of... | KEEP AS NON CORE | Summary: IFIT3 (RIG-G) mediates antiproliferative effects of interferon through p21/p27. This is a documented function, though secondary to antiviral role. Supporting Evidence: PMID:17050680 RIG-G as a key mediator of the antiproliferative activity of interferon-related pathways through enhancing p21 and p27 proteins |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:21190939 The interferon stimulated gene 54 promotes apoptosis. | ACCEPT | Summary: IFIT3 (ISG60) negatively regulates IFIT2 (ISG54)-mediated apoptosis. This is a core function that distinguishes IFIT3 from the pro-apoptotic IFIT2. Supporting Evidence: PMID:21190939 In addition, ISG60 binding negatively regulates the apoptotic effects of ISG54 file:human/IFIT3/IFIT3-deep-research-perplexity.md IFIT3 interacts with IFIT2 and negatively regulates the apoptotic effects of IFIT2 |
| GO:0009615 response to virus | IMP PMID:21642987 IFIT1 is an antiviral protein that recognizes 5'-triphosphat... | ACCEPT | Summary: Mutant phenotype evidence for viral response function. Supporting Evidence: PMID:21642987 In the absence of IFIT1, the growth and pathogenicity of viruses containing PPP-RNA was much greater. In contrast, IFIT proteins were dispensable for the clearance of pathogens that did not generate PPP-RNA |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1015702 | ACCEPT | Summary: Reactome annotation for cytosolic localization in IFN response. Supporting Evidence: file:human/IFIT3/IFIT3-deep-research-perplexity.md IFIT3 exhibits characteristically diffuse, total cytoplasmic localization in both uninfected cells expressing the protein exogenously and in cells treated with interferon-alpha |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:21813773 IFN-induced TPR protein IFIT3 potentiates antiviral signalin... | NEW | Summary: IFIT3 functions as a scaffold protein that bridges MAVS and TBK1 at mitochondria, amplifying interferon signaling. This adaptor activity stabilizes MAVS-TBK1 interactions leading to enhanced IRF3 phosphorylation and IFN-beta production. Reason: Core molecular function - IFIT3 serves as an adaptor bringing together MAVS and TBK1 in the antiviral signaling pathway. Supporting Evidence: PMID:21813773 the tetratrico-peptide repeat motif (E164/E165) of IFIT3 interacts with the N terminus (K38) of TBK1, thus bridging TBK1 to MAVS on the mitochondrion. Disruption of this interaction markedly attenuates the activation of TBK1 and IRF3 file:human/IFIT3/IFIT3-deep-research-perplexity.md IFIT3 bridges MAVS and TBK1 at mitochondria to amplify interferon signaling, stabilizing MAVS-TBK1 interactions |
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Download this section (compressed HTML)Q: How does IFIT3 achieve the conformational change in IFIT1 that enhances cap-0 specificity while reducing 5'-ppp RNA binding?
Q: What determines whether IFIT3 promotes antiviral restriction or facilitates viral replication in specific host-pathogen contexts?
Experiment: Determine the structure of the IFIT1-IFIT3 complex bound to cap-0 RNA to understand the allosteric mechanism by which IFIT3 enhances IFIT1 specificity.
Type: structural biology
Experiment: Compare antiviral efficacy of IFIT3 wild-type versus YxxxL motif mutants against viruses with different cap structures to delineate complex-dependent vs independent functions.
Type: functional assay
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