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Details on Person Interferon-induced protein with tetratricopeptide repeats 1 ...
| Class:Id | Summation:9684530 |
|---|---|
| _displayName | Interferon-induced protein with tetratricopeptide repeats 1 ... |
| _timestamp | 2025-10-13 15:56:45 |
| created | [InstanceEdit:9684507] Shamovsky, Veronica, 2020-04-21 |
| literatureReference | [LiteratureReference:9684457] Sequestration by IFIT1 impairs translation of 2'O-unmethylated capped RNA [LiteratureReference:9684553] Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability [LiteratureReference:9690575] 2'-O methylation of the viral mRNA cap evades host restriction by IFIT family members [LiteratureReference:9684483] IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA [LiteratureReference:9684537] IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA [LiteratureReference:9968364] SARS-CoV-2 Uses Nonstructural Protein 16 To Evade Restriction by IFIT1 and IFIT3 [LiteratureReference:9968355] Nsp16 shields SARS-CoV-2 from efficient MDA5 sensing and IFIT1-mediated restriction [LiteratureReference:9684462] Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-o-methyltransferase activity [LiteratureReference:9684554] Rational design of a live attenuated dengue vaccine: 2'-o-methyltransferase mutants are highly attenuated and immunogenic in mice and macaques [LiteratureReference:9968137] Cap-related modifications of RNA regulate binding to IFIT proteins [LiteratureReference:9968359] 2'-O methylation of the viral mRNA cap by West Nile virus evades ifit1-dependent and -independent mechanisms of host restriction in vivo [LiteratureReference:9684534] Protective roles of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in dengue virus infection of human lung epithelial cells |
| modified | [InstanceEdit:9690558] Shamovsky, Veronica, 2020-06-03 [InstanceEdit:9690680] Shamovsky, Veronica, 2020-06-03 [InstanceEdit:9690771] Shamovsky, Veronica, 2020-06-06 [InstanceEdit:9691468] Shamovsky, Veronica, 2020-06-16 [InstanceEdit:9691481] Shamovsky, Veronica, 2020-06-16 [InstanceEdit:9692472] Shamovsky, Veronica, 2020-06-24 [InstanceEdit:9713664] Shamovsky, Veronica, 2021-01-28 [InstanceEdit:9968367] Shamovsky, Veronica, 2025-10-13 |
| text | Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) forms a stable complex with IFIT3 through a conserved C-terminal YxxxL motif, an interaction that enhances IFIT1 antiviral activity (Johnson B et al. 2018; Fleith RC et al. 2018). IFIT1 detects and sequesters single-stranded viral RNAs lacking 2′-O methylation at their 5′ end, including uncapped 5′-triphosphate (5′-ppp) RNA and cap-0 structures (m⁷GpppN, guanine N7 methylated but not ribose 2′-O methylated). By doing so, IFIT1 competes with the eukaryotic initiation factor 4F (eIF4F) cap-binding complex, preventing 43S pre-initiation complex assembly and blocking viral protein synthesis (Daffis S et al. 2010; Pichlmair A et al. 2011; Habjan M et al. 2013). Crystal structures, hydrogen–deuterium exchange mass spectrometry (HDX-MS), and quantitative filter-binding assays showed that IFIT3 enhances IFIT1 affinity for cap-0 RNA while strongly reducing binding to 5′-ppp RNA (Johnson B et al. 2018). Primer extension inhibition assays further confirmed enhanced recognition of cap-0 RNA by IFIT1:IFIT3 complexes (Fleith RC et al. 2018), while biolayer interferometry (BLI) revealed that IFIT3 also increased IFIT1 binding to a broader range of capped RNA species, including cap-1 (m⁷GpppNm), albeit with much lower affinity than for cap-0 (Geng J et al. 2024). Viral 2′-O-methyltransferase (2′-O-MTase) activity encoded by flaviviruses (e.g., West Nile virus, WNV), poxvirus (Vaccinia virus), and betacoronaviruses (e.g., SARS-CoV-1, SARS-CoV-2) inhibits IFIT1 function, while 2′-O-MTase-defective viruses exhibit attenuated replication that depends on IFIT1 recognition (Daffis S et al. 2010; Hsu YL et al. 2013; Züst R et al. 2013; Menachery VD et al. 2014; Johnson B et al. 2018; Russ A et al. 2022; Schindewolf C et al. 2023). Importantly, co-expression of IFIT3 enhanced IFIT1-mediated antiviral restriction in human embryonic kidney HEK293T cells infected with 2′-O-MTase-deficient WNV (Johnson B et al. 2018) or Zika virus (ZIKV) mutants (Johnson B et al. 2018), as well as in human respiratory cells infected with SARS-CoV-2 mutants lacking 2′-O methylation (Schindewolf C et al. 2023). In addition, IFIT3 stabilizes IFIT1 protein levels in HEK293T cells (Fleith R.C. et al. 2018). In vivo studies with 2′-O-MTase mutants of WNV, SARS-CoV-1, and SARS-CoV-2 further confirmed that loss of methylation leads to reduced virulence in an IFIT-dependent manner (Daffis S et al. 2010; Szretter KJ et al. 2012; Menachery VD et al. 2014; Schindewolf C et al. 2023). Collectively, these findings suggest that IFIT3 enhances IFIT1 function both by stabilizing IFIT1 and by tuning its RNA-binding channel to selectively target cap-0 RNAs. This Reactome event describes the binding of IFIT1:IFIT3 to viral cap-0 (m⁷G(5′)pppN) RNAs lacking a 2′-O-methyl group. This recognition is inhibited by viral 2′-O-MTase activity in WNV, SARS-CoV-1, and SARS-CoV-2, although the role of IFIT3 in IFIT1-mediated restriction of SARS-CoV-1 requires further study (Daffis S et al. 2010; Menachery VD et al. 2014; Schindewolf C et al. 2023). |
| (summation) | [Reaction:9684493] IFIT1:IFIT3 binds viral m7G(5')pppN-mRNA [Homo sapiens] |
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