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Details on Person During viral infection, the antiviral innate immune response...
| Class:Id | Summation:9684513 |
|---|---|
| _displayName | During viral infection, the antiviral innate immune response... |
| _timestamp | 2025-10-10 13:22:46 |
| created | [InstanceEdit:9684507] Shamovsky, Veronica, 2020-04-21 |
| literatureReference | [LiteratureReference:9684483] IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA [LiteratureReference:9684546] Inhibition of translation by IFIT family members is determined by their ability to interact selectively with the 5'-terminal regions of cap0-, cap1- and 5'ppp- mRNAs [LiteratureReference:9684457] Sequestration by IFIT1 impairs translation of 2'O-unmethylated capped RNA [LiteratureReference:9684505] Structure of human IFIT1 with capped RNA reveals adaptable mRNA binding and mechanisms for sensing N1 and N2 ribose 2'-O methylations [LiteratureReference:9684464] Structural basis for viral 5'-PPP-RNA recognition by human IFIT proteins [LiteratureReference:9690560] Kinetic analysis of IFIT1 and IFIT5 interactions with different native and engineered RNAs and its consequences for designing mRNA-based therapeutics [LiteratureReference:9684553] Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability [LiteratureReference:9968137] Cap-related modifications of RNA regulate binding to IFIT proteins [LiteratureReference:9684537] IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA [LiteratureReference:9684455] Better together: the role of IFIT protein-protein interactions in the antiviral response [LiteratureReference:9691507] Human and Murine IFIT1 Proteins Do Not Restrict Infection of Negative-Sense RNA Viruses of the Orthomyxoviridae, Bunyaviridae, and Filoviridae Families [LiteratureReference:9690575] 2'-O methylation of the viral mRNA cap evades host restriction by IFIT family members |
| modified | [InstanceEdit:9690570] Shamovsky, Veronica, 2020-06-03 [InstanceEdit:9690685] Shamovsky, Veronica, 2020-06-04 [InstanceEdit:9690771] Shamovsky, Veronica, 2020-06-06 [InstanceEdit:9691522] Shamovsky, Veronica, 2020-06-17 [InstanceEdit:9692472] Shamovsky, Veronica, 2020-06-24 [InstanceEdit:9755792] Shamovsky, Veronica, 2021-10-11 [InstanceEdit:9968138] Shamovsky, Veronica, 2025-10-10 |
| text | During viral infection, the antiviral innate immune response effector IFIT1 (interferon-induced protein with tetratricopeptide repeats 1, also known as IFN-induced 56 kDa protein) restricts viral replication by recognizing RNAs that lack the host’s characteristic 2′-O methylation at the 5′ cap (Daffis S et al., 2010; Pichlmair A et al. 2011; Habjan M et al. 2013; Kumar P et al. 2014). This includes uncapped 5′-triphosphate RNAs (5’-ppp-RNA), which can be found during the replication of single-stranded RNA viruses such as influenza A virus (IAV) and vesicular stomatitis virus (VSV). IFIT1 was shown to precipitate viral RNAs from human embryonic kidney 293T (HEK293) cells infected with VSV or IAV, and to restrict VSV infection in vivo (Pichlmair A et al. 2011). In IFIT1-overexpressing HEK293 cell lysates, affinity pulldown assays using synthetic 5′-triphosphate RNA beads, together with electrophoretic mobility shift assays (EMSAs), confirmed direct binding of IFIT1 to uncapped 5′-triphosphate RNA (Pichlmair A et al. 2011; Abbas YM et al. 2013). IFIT1 mutants lacking the ability to bind 5′-ppp RNA displayed impaired antiviral activity in IAV-infected HEK293T cells compared with wild-type IFIT1 (Abbas YM et al. 2013). Although IFIT1 can recognize 5′-ppp RNA, its affinity for this RNA structure is markedly lower than for capped RNA lacking 2′-O methylation at the first cap proximal nucleotide (cap-0, m⁷GpppN) (Pichlmair A et al. 2011; Kumar P et al. 2014; Abbas YM et al. 2013, 2017; Johnson B et al. 2018; Miedziak B et al. 2020; ). Kinetic studies showed that both GpppN (an uncapped RNA analog) and cap-0 RNAs form the most stable complexes with IFIT1 (Kumar P et al. 2014; Miedziak B et al. 2020). Crystal structures revealed that IFIT1 contains a positively charged, water-filled RNA-binding tunnel between the N- and C-terminal domains, which interacts with single-stranded RNA through electrostatic interactions. Additionally, a large hydrophobic cavity accommodates the cap structure via van der Waals contacts (Abbas YM et al. 2013, 2017). The antiviral activity of IFIT1 is enhanced by IFIT3, which binds IFIT1 with nanomolar affinity (Johnson B et al. 2018; Fleith R et al. 2018; Geng J et al. 2024). IFIT3 enhances IFIT1's affinity for cap-0 RNA by allosterically stabilizing its RNA-binding channel and extending IFIT1 protein half-life, while reducing any residual binding of IFIT1 to 5′-ppp RNA, rendering it nearly undetectable (Johnson B et al., 2018; Fleith RC et al., 2018). Host mRNAs, which are typically 2′-O methylated at the first or second nucleotide downstream of the cap (cap-1/cap-2), avoid IFIT1 recognition due to steric clashes in the RNA-binding tunnel that prevent their stable binding (Abbas Y.M. et al. 2017). IFIT1 binding to non-self RNAs lacking proper methylation sequesters these RNA species from the eIF4F cap-binding complex, blocking 43S pre-initiation complex assembly, thereby inhibiting viral protein synthesis (Habjan M et al. 2013; Kumar P et al. 2014). IFIT1 can self-associate through tetratricopeptide repeat (TPR) motifs to form dimers and higher-order oligomers, as shown by native gel electrophoresis, size-exclusion chromatography, and crystallography (Kumar P et al. 2014; Abbas YM et al. 2017). Oligomerization is thought to enhance RNA-binding capacity (Kumar P et al. 2014; Mears HV & Sweeney TR 2018). Here we show antiviral activity of IFIT1 through binding to viral 5′-ppp RNA. However, IFIT1 effect can be cell-type and virus specific, with reports of limited restriction for some negative-sense RNA viruses in human alveolar basal epithelial (A549) cells (Pinto AK et al. 2015). |
| (summation) | [Reaction:9684484] IFIT1 binds viral 5'-ppp-RNA [Homo sapiens] |
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