| 2025 |
Cryo-EM structure of the IFIT2-IFIT3 complex at 3.2 Å reveals a domain-swapped heterodimer; this complex recognizes viral mRNAs bearing short 5' UTRs (<50 nucleotides) as a molecular pattern for innate immune recognition, inhibits their translation, and confers antiviral activity against viruses such as VSV and parainfluenza virus 3. |
Cryo-EM structure determination (3.2 Å), in vitro translation inhibition assays, antiviral activity assays with recombinant viruses, 5' UTR length-swap reporter experiments |
Nature microbiology |
High |
41093992
|
| 2025 |
IFIT2-IFIT3 heterodimer binds directly to the VEEV 3' UTR in vitro; 5' UTR lengths <50 nucleotides are necessary and sufficient for translation inhibition by the IFIT2-IFIT3 complex, independent of cap structure. |
In vitro RNA-binding assays, recombinant VEEV clones with swapped 3' UTRs, in vitro translation inhibition assays |
Journal of interferon & cytokine research |
Medium |
40079162
|
| 2018 |
IFIT1 and IFIT3 interact via a YxxxL motif in their C-termini; IFIT2 and IFIT3 form homodimers that dissociate to yield a more stable IFIT2-IFIT3 heterodimer, which also associates with IFIT1. IFIT3 stabilizes IFIT1 protein expression, promotes IFIT1 binding to cap0 Zika virus reporter mRNA, and enhances IFIT1-mediated translation inhibition. |
In vitro reconstitution of IFIT complexes, cap0 mRNA-binding assay, translation inhibition assay, site-directed mutagenesis of YxxxL motif |
Nucleic acids research |
High |
29554348
|
| 2020 |
IFIT2 binds directly to viral and cellular mRNAs in AU-rich regions (demonstrated by CLIP-seq during influenza virus infection); ribosome/polysome profiling showed that IFIT2 prevents ribosome pausing on bound mRNAs, thereby enhancing translational efficiency. Influenza virus repurposes this activity to promote viral mRNA translation and replication. |
CLIP-seq, polysome profiling, ribosome profiling, CRISPR-Cas9 knockout screen |
Nature microbiology |
High |
32839537
|
| 2024 |
IFIT2 RNA-binding activity is essential for its antiviral function in vivo: mice expressing a mutant IFIT2 that cannot bind RNA were as susceptible to intranasal VSV infection as Ifit2−/− mice. Additionally, neuron-specific conditional knockout of Ifit2 was sufficient to render mice susceptible to VSV neuropathogenesis via the intranasal (but not subcutaneous) route, placing IFIT2 function specifically in neurons. |
Conditional knockout mouse (neuron-specific Cre), RNA-binding mutant knock-in mouse, intranasal/subcutaneous VSV challenge, survival and viral load analysis |
mBio |
High |
38888342
|
| 2006 |
GARG39/IFIT2 protein interacts with microtubules in vitro, co-localizes with β-tubulin in vivo, and is enriched in the mitotic spindle of non-neuronal cells undergoing mitosis, identifying it as a microtubule-associated protein. |
In vitro microtubule binding assay, immunofluorescence co-localization with β-tubulin, mitotic cell imaging |
The Journal of general virology |
Medium |
17030862
|
| 2017 |
Proteasome inhibition blocks IFIT2 degradation and causes IFIT2 to aggregate at the centrosome; this aggregation depends on intact microtubule dynamics (colchicine-sensitive) and dynein activity (ciliobrevin-sensitive). IFIT2 combined with proteasome inhibitor synergistically induces cancer cell apoptosis. |
Immunofluorescence localization after proteasome inhibitor treatment, pharmacological inhibition of microtubules (colchicine) and dynein (ciliobrevin), apoptosis assay |
International journal of biological sciences |
Medium |
28367102
|
| 2018 |
IFIT2 is a binding partner of p67phox, a critical regulatory subunit of NADPH oxidase; loss of IFIT2 increases ROS production by leukocytes, suggesting IFIT2 suppresses NADPH oxidase activation. Ifit2 knockout mice showed improved survival and reduced fungal burden in a systemic Candida albicans model. |
Co-immunoprecipitation/binding partner identification, ROS measurement in Ifit2-knockout leukocytes, in vivo C. albicans infection survival study |
mBio |
Medium |
29666281
|
| 2013 |
Ifit2 deficiency in macrophages impairs IFN-α/β mRNA and protein production following MHV coronavirus infection, placing Ifit2 as a positive regulator of IFN-α/β induction (rather than solely a direct antiviral effector) in macrophages during coronavirus CNS infection. |
Ifit2−/− mouse model, ex vivo microglia/macrophage analysis, IFN-α/β mRNA and protein quantification in bone marrow-derived macrophages, in vivo viral load measurement |
Journal of virology |
Medium |
24198415
|
| 2011 |
IKKε phosphorylates STAT1 at serine 708, which is required for IFIT2 expression; loss of IKKε abrogates IFIT2 induction and enhances WNV replication. STAT1 tyrosine dephosphorylation and CRM1-mediated nuclear-cytoplasmic shuttling are prerequisites for Ser-708 phosphorylation. This defines an IFN-induced IKKε→STAT1(Ser708)→IFIT2 signaling axis. |
IKKε−/− and IFIT2−/− cell/mouse models, STAT1 phosphorylation analysis (site-specific antibodies), CRM1 inhibitor (leptomycin B) treatment, WNV infection assays |
The Journal of biological chemistry |
Medium |
22065572
|
| 2013 |
IFIT2 promotes IRF3 phosphorylation, thereby amplifying LPS-induced IFN-β production and subsequent IL-6/TNF-α secretion (post-transcriptionally). Ifit2-deficient mice show reduced serum IL-6 and TNF-α and reduced mortality in endotoxin shock. IFIT2 expression is induced in an IFN-α receptor- and IRF9-dependent manner. |
Ifit2−/− mouse generation, bone marrow-derived macrophage cytokine assays (ELISA), IRF3 phosphorylation western blotting, LPS endotoxin shock model |
Journal of immunology |
Medium |
24014876
|
| 2008 |
Overexpression of IFIT2 in macrophages selectively reduces LPS-induced TNF-α, IL-6, and MIP-2 expression by decreasing mRNA stability at the post-transcriptional level; characteristics of the 3' UTR of transcripts determine susceptibility to IFIT2-mediated regulation. |
Stable IFIT2-overexpressing RAW264.7 macrophage lines, mRNA stability assay (actinomycin D chase), ELISA, western blot |
BMC immunology |
Medium |
19108715
|
| 2012 |
Depletion of IFIT2 in oral squamous cell carcinoma cells activates atypical PKC (aPKC), leading to epithelial-mesenchymal transition, enhanced cell migration, and invasiveness. Inhibition of aPKC (by pseudosubstrate or siRNA) abolished these phenotypes, placing aPKC downstream of IFIT2. |
Stable IFIT2 shRNA knockdown cell lines, aPKC pseudosubstrate inhibitor treatment, siRNA knockdown of aPKC, migration/invasion assays, tail-vein metastasis model |
Oncogene |
Medium |
22986528
|
| 2016 |
AJUBA binds directly to the FERM domain of JAK1, dissociating JAK1 from the IFN-γ receptor and thereby inhibiting STAT1 phosphorylation and nuclear translocation, which represses IFIT2 gene expression and inhibits apoptosis in colorectal cancer cells. |
Co-immunoprecipitation (AJUBA-JAK1 binding), STAT1 phosphorylation assay, IFIT2 promoter/expression analysis, apoptosis assays, siRNA knockdown |
Oncogene |
Medium |
27893714
|
| 2022 |
METTL3 mediates m6A modification of IFIT2 mRNA, which accelerates IFIT2 mRNA decay in a YTHDF2-dependent manner in intrahepatic cholangiocarcinoma. METTL3 transcription itself is driven by H3K4me3 activation. |
METTL3 knockdown/overexpression, MeRIP-seq (m6A mapping), YTHDF2 knockdown rescue experiments, mRNA stability assays, ChIP-seq for H3K4me3 |
Oncogene |
Medium |
35094011
|
| 2012 |
Ifit2 is required for protection against lethal VSV neuropathogenesis following intranasal infection in mice. Ifit2−/− mice show several-hundred-fold higher VSV titers in the brain (without broadened cell tropism) compared to wild-type or Ifit1−/− mice, establishing Ifit2 as a tissue- and virus-specific ISG antiviral effector in the CNS. |
Ifit2−/− and Ifit1−/− knockout mouse infection models (intranasal VSV), viral titer quantification in CNS and peripheral organs, neurological phenotyping |
PLoS pathogens |
High |
22615570
|
| 2014 |
Ifit2 protects peripheral nervous system neurons from VSV infection after subcutaneous footpad injection. In Ifit2−/− mice, VSV spread from lymph node to sciatic nerve, spinal cord, and brain causing paralysis, whereas in wild-type mice this neuronal spread was blocked despite equivalent viral replication in the lymph node. |
Ifit2−/− mouse model, subcutaneous footpad VSV injection, viral titer in lymph node, sciatic nerve, spinal cord, and brain, neurological outcome assessment |
Journal of virology |
High |
24991014
|
| 2017 |
PLZF increases STAT1 protein levels, which drives IFIT2 mRNA transcription; ablation of IFIT2 in PLZF-overexpressing gallbladder cancer cells partially abrogates the tumor-suppressive effect of PLZF (reduced growth, EMT inhibition), placing IFIT2 downstream of PLZF/STAT1 in a growth-suppressive pathway. |
PLZF overexpression, IFIT2 shRNA knockdown in PLZF-OE cells (epistasis), STAT1 western blot, RT-PCR, xenograft mouse model |
Cell death & disease |
Medium |
29358655
|
| 1996 |
GARG-39 (murine IFIT2 homolog) was identified as a protein containing 10 tetratricopeptide repeat (TPR) domains, induced by LPS and interferons (α/β and γ) in macrophages. The TPR domain architecture was predicted to mediate protein-protein interactions in multicomponent assemblies. |
cDNA cloning, sequence analysis of TPR domains, northern blot induction assays in 3T3 cells and macrophages with LPS/IFN stimulation |
Archives of biochemistry and biophysics |
Medium |
8660659
|
| 2024 |
IFIT2 knockdown in foamy macrophages attenuates ox-LDL-induced iron retention (reduces ferritin-L, ferritin-H, Fe2+ and Fe3+) and promotes cholesterol efflux via upregulation of PPARγ/LXRα/ABCA1/ABCG1 pathway; in vivo Ifit2 knockdown in atherosclerotic APOE−/− mice reduces plaque area and lipid accumulation. |
shRNA lentivirus knockdown in HFD-induced APOE−/− mice (in vivo), ox-LDL-induced foamy macrophage model (in vitro), western blot for iron/cholesterol efflux proteins, iron measurement |
International immunopharmacology |
Medium |
39276454
|
| 2020 |
IFIT2 overexpression in K562 chronic myeloid leukemia cells inhibits cell proliferation and causes G1 arrest by inhibiting the BCR-ABL oncoprotein and its downstream AKT/mTOR signaling, and by inducing p27kip1 via degradation of cullin1-mediated E3 ligases. |
Stable IFIT2-overexpressing K562 cell line, cell cycle analysis, western blot for BCR-ABL, p-AKT, p-mTOR, p27kip1, and cullin1 |
International journal of molecular medicine |
Low |
32124954
|
| 2025 |
IRF1 directly binds to the IFIT2 gene promoter and activates its transcription, as validated by promoter-reporter (luciferase) assay and protein-binding microarray mapping of IRF1 binding motifs. |
Luciferase reporter assay with IFIT2 promoter constructs, protein-binding microarray, IRF1 knockout and overexpression in HeLa cells, RNA-seq |
bioRxiv (preprint)preprint |
Low |
|
| 2024 |
Biophysical characterization shows that cap-adjacent m6Am modification on RNA strongly blocks formation of the IFIT protein complex with RNA; the IFIT2-IFIT3 interaction (and IFIT1-IFIT3 interaction at nanomolar affinity) was characterized with kinetic parameters. m6A within the 5'UTR (not at cap) is not recognized by IFIT proteins and does not contribute to translation repression. |
Biophysical binding assays (SPR/ITC-type kinetics), RNA with defined 5'-cap modifications, IFIT protein complex reconstitution |
bioRxiv (preprint)preprint |
Low |
|