IFIT2 (ISG54) is an interferon-stimulated gene encoding a multifunctional protein with tetratricopeptide repeat (TPR) motifs. The protein functions as a critical component of innate antiviral immunity through multiple mechanisms: binding AU-rich RNA sequences, forming heterocomplexes with IFIT1 and IFIT3 to enhance antiviral activity, and interacting with eIF3 to inhibit translation of unmethylated viral mRNAs. Beyond antiviral functions, IFIT2 directly promotes mitochondrial apoptosis through BCL2 family proteins (BAX/BAK-dependent). The protein exists as a domain-swapped homodimer and is strongly induced by type I and III interferons via JAK-STAT signaling and IRF3. IFIT2 is downregulated in multiple cancer types where it acts as a tumor suppressor by inhibiting proliferation and promoting apoptosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003723 RNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: RNA binding is a core function of IFIT2. The protein binds AU-rich RNA sequences through a positively charged nucleotide-binding channel in its C-terminal subdomain. Supporting Evidence: file:human/IFIT2/IFIT2-deep-research-perplexity.md IFIT2 displays a strong preference for binding to AU-rich double-stranded RNA and AU-rich adenosine-uridine-rich sequences (AREs) present in the 3' untranslated regions of many unstable mRNAs |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Cytosolic localization is confirmed by multiple studies. Supporting Evidence: file:human/IFIT2/IFIT2-deep-research-perplexity.md IFIT2 shows cytoplasmic expression in immune cells |
| GO:0071345 cellular response to cytokine stimulus | IBA GO_REF:0000033 | ACCEPT | Summary: IFIT2 is an interferon-stimulated gene, induced by type I/III interferons through JAK-STAT signaling. This is a core regulatory process. Supporting Evidence: file:human/IFIT2/IFIT2-deep-research-perplexity.md The IFIT2 gene is fundamentally classified as a type I interferon-stimulated gene (ISG) whose expression is tightly coupled to the production of type I interferons |
| GO:0140374 antiviral innate immune response | IBA GO_REF:0000033 | ACCEPT | Summary: Antiviral innate immune response is a core function of IFIT2. The protein restricts viral replication through RNA binding and translation inhibition. Supporting Evidence: file:human/IFIT2/IFIT2-deep-research-perplexity.md IFIT2 is a multifunctional interferon-stimulated gene product that functions as a critical component of the innate antiviral immune response |
| GO:0002376 immune system process | IEA GO_REF:0000043 | ACCEPT | Summary: General parent term for immune function. More specific terms are preferred. |
| GO:0003723 RNA binding | IEA GO_REF:0000043 | ACCEPT | Summary: Consistent with IBA annotation. RNA binding is well-supported. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasmic localization is correct and well-supported. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: ER localization is reported but appears to be a secondary localization. Primary functional location is cytosol. Supporting Evidence: file:human/IFIT2/IFIT2-deep-research-perplexity.md IFIT2 is located in the endoplasmic reticulum and is expressed in the cytoplasm |
| GO:0006915 apoptotic process | IEA GO_REF:0000043 | MODIFY | Summary: IFIT2 promotes apoptosis through mitochondrial pathway. More specific term (positive regulation of apoptotic process) is preferred. Proposed replacements: positive regulation of apoptotic process |
| GO:0045087 innate immune response | IEA GO_REF:0000043 | ACCEPT | Summary: Correct. IFIT2 is a key innate immune effector induced by interferons. |
| GO:0051607 defense response to virus | IEA GO_REF:0000120 | ACCEPT | Summary: Defense response to virus is a core function. IFIT2 restricts viral replication particularly for viruses with unmethylated RNA caps. Supporting Evidence: file:human/IFIT2/IFIT2-deep-research-perplexity.md IFIT2 functions as a promoter of mitochondrial apoptosis through a pathway dependent on BCL2 family proteins, and its downregulation in multiple cancer types correlates with enhanced cell proliferation |
| GO:0005515 protein binding | IPI PMID:19416887 ISG56 is a negative-feedback regulator of virus-triggered si... | REMOVE | Summary: This paper shows IFIT2 interacts with IFIT1 as part of antiviral response. Generic protein binding is uninformative per curation guidelines. Reason: Generic protein binding; specific IFIT1 interaction better captured by complex annotations. Supporting Evidence: PMID:19416887 we identified ISG56 and ISG54 as two proteins associated with MITA, a critical adapter protein involved in virus-triggered induction of type I IFNs |
| GO:0005515 protein binding | IPI PMID:21642987 IFIT1 is an antiviral protein that recognizes 5'-triphosphat... | REMOVE | Summary: Paper focuses on IFIT1 RNA binding. Generic protein binding uninformative. Reason: Generic protein binding per curation guidelines. 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:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: High-throughput interactome study. Generic protein binding uninformative. Reason: High-throughput study; generic protein binding per curation guidelines. Supporting Evidence: PMID:28514442 Here we present BioPlex 2.0 (Biophysical Interactions of ORFeome-derived complexes), which uses robust affinity purification-mass spectrometry methodology to elucidate protein interaction networks |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Population genetics study on protein interactions. Generic term uninformative. Reason: Generic protein binding per curation guidelines. Supporting Evidence: PMID:31515488 we leveraged the ExAC dataset of coding variants from 60,706 human exomes9 to systematically evaluate the impact of 2009 missense SNVs, 811 of which are segregating at minor allele frequency (MAF) > 0.1% in human populations, across 2185 proteinβprotein interactions |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: BioPlex interactome study. Generic protein binding uninformative. Reason: High-throughput study; generic protein binding per curation guidelines. Supporting Evidence: PMID:33961781 we have created two proteome-scale, cell-line-specific interaction networks. The first, BioPlex 3.0, results from affinity purification of 10,128 human proteins-half the proteome-in 293T cells and includes 118,162 interactions among 14,586 proteins |
| GO:0140374 antiviral innate immune response | IDA PMID:31390091 TRAF3IP3 mediates the recruitment of TRAF3 to MAVS for antiv... | ACCEPT | Summary: Direct experimental evidence for antiviral innate immune function. This study shows TRAF3IP3 recruits TRAF3 to MAVS for antiviral innate immunity. Supporting Evidence: PMID:31390091 ISG54 but not IL-6 induction was impaired in Traf3ip3 β/β cells, indicating that TRAF3IP3 was indeed required for TBK1-IRF3 but not IKK-NF-ΞΊB activation and nevertheless essential for IFNs induction |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | ACCEPT | Summary: High-throughput RNA-binding protein identification study confirms IFIT2 as RNA-binding protein. Core molecular function. Supporting Evidence: PMID:22658674 May 31. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. |
| GO:0005737 cytoplasm | IDA PMID:21190939 The interferon stimulated gene 54 promotes apoptosis. | ACCEPT | Summary: Direct experimental evidence for cytoplasmic localization. Supporting Evidence: PMID:21190939 2010 Dec 29. The interferon stimulated gene 54 promotes apoptosis. |
| GO:0140374 antiviral innate immune response | IDA PMID:19416887 ISG56 is a negative-feedback regulator of virus-triggered si... | ACCEPT | Summary: This paper (ISG56 is a negative-feedback regulator of virus-triggered signaling) provides direct evidence for antiviral function. Supporting Evidence: PMID:19416887 ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1015702 | ACCEPT | Summary: Reactome annotation confirming cytosolic localization during IFN response. |
| GO:0005515 protein binding | IPI PMID:21190939 The interferon stimulated gene 54 promotes apoptosis. | REMOVE | Summary: This paper shows IFIT2 promotes apoptosis. The protein binding annotation is too generic; the functional finding is apoptosis promotion. Reason: Generic protein binding; apoptosis function captured by other terms. Supporting Evidence: PMID:21190939 2010 Dec 29. The interferon stimulated gene 54 promotes apoptosis. |
| GO:0005783 endoplasmic reticulum | IDA PMID:21190939 The interferon stimulated gene 54 promotes apoptosis. | KEEP AS NON CORE | Summary: Direct evidence for ER localization. Secondary localization. Supporting Evidence: PMID:21190939 2010 Dec 29. The interferon stimulated gene 54 promotes apoptosis. |
| GO:0008637 apoptotic mitochondrial changes | TAS PMID:21190939 The interferon stimulated gene 54 promotes apoptosis. | ACCEPT | Summary: IFIT2 promotes mitochondrial apoptosis through BAX/BAK-dependent pathway. This is a core function. Supporting Evidence: PMID:21190939 The interferon stimulated gene 54 promotes apoptosis file:human/IFIT2/IFIT2-deep-research-perplexity.md both BAX and BAK, two essential effector proteins in the mitochondrial apoptosis pathway, are required for IFIT2-mediated apoptosis |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:21190939 The interferon stimulated gene 54 promotes apoptosis. | ACCEPT | Summary: Direct experimental evidence that IFIT2 promotes apoptosis. Core function distinct from other IFIT family members. Supporting Evidence: PMID:21190939 The interferon stimulated gene 54 promotes apoptosis file:human/IFIT2/IFIT2-deep-research-perplexity.md IFIT2 directly promotes apoptosis through a mitochondrial pathway dependent on BCL2 family proteins |
| 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 IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA. |
| GO:0009615 response to virus | IDA PMID:19416887 ISG56 is a negative-feedback regulator of virus-triggered si... | ACCEPT | Summary: Direct experimental evidence for antiviral function. Supporting Evidence: PMID:19416887 ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response. |
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Download this section (compressed HTML)Q: How does the balance between IFIT2's antiviral and pro-apoptotic functions contribute to the outcomes of viral infection in different cell types?
Q: What structural features distinguish IFIT2's AU-rich RNA binding specificity from the cap0-mRNA binding of IFIT1?
Experiment: Compare the antiviral efficacy of IFIT2 wild-type versus RNA-binding mutants (R287E, K405E) against different classes of viruses to determine the relative contribution of RNA binding to antiviral function.
Type: functional assay
Experiment: Characterize the stoichiometry and assembly pathway of IFIT1:IFIT2:IFIT3 heterocomplexes to understand how complex composition affects antiviral activity.
Type: protein interaction
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