Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability

Johnson, Britney; VanBlargan, Laura A.; Xü, Wei; White, James P.; Shan, Chao; Shi, Pei Yong; Zhang, Rong; Adhikari, Jagat; Gross, Michael L.; Leung, Daisy W.; Diamond, Michael S.; Amarasinghe, Gaya K.

doi:10.1016/j.immuni.2018.01.014

Cited by 97 publications

(166 citation statements)

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“…mRNAs that lack Cap 1 2’O methylation are known to be preferentially bound by IFIT1 (13, 19-22, 25, 27, 30, 42), and the translation of viral RNAs lacking Cap 1 2’O methylation is known to be inhibited by IFIT1 (20, 21, 42). Therefore, we hypothesized that the protein expression of host transcripts lacking Cap 1 2’O methylation may be inhibited by IFIT1.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, we found that depletion of IFIT1 rescued the protein expression of ISG15, MX1, and IFITM1 resulting in equivalent expression of ISGs following CMTR1 depletion as compared to control in IFN-β-treated Huh7 cells ( Figure 4-B ). We did not examine IFIT3 in this assay, as it is in a complex with IFIT1 alterations in IFIT1 levels likely also IFIT3 expression (20, 21, 43). Therefore, the translational repression of the CMTR1-dependent ISGs is mediated through the actions of IFIT1.…”

Section: Resultsmentioning

confidence: 99%

“…RIG-I binding to Cap 0 mRNA can activate a signaling cascade that induces an IFN response (12, 16), whereas IFIT1 binding to Cap 0 mRNA inhibits its translation (13, 17-19). This translational inhibition by IFIT1 is in part mediated by its interaction with the IFN-induced protein IFIT3, which increases the specificity of IFIT1 for Cap 0 mRNAs (20-22). As such, many viruses have evolved mechanisms to evade RIG-I and IFIT1 sensing of their 5’ RNA ends.…”

Section: Introductionmentioning

confidence: 99%

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The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

Williams

Gokhale

Snider

et al. 2020

Preprint

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AbstractType I interferons (IFN) initiate an antiviral state through a signal transduction cascade that leads to the induction of hundreds of IFN-stimulated genes (ISGs) to restrict viral infection. Recently, RNA modifications on both host and viral RNAs have been described as regulators of infection. However, the impact of host mRNA cap modifications on the IFN response and how this regulates viral infection is unknown. Here, we reveal that CMTR1, an ISG that catalyzes 2’O methylation of the first transcribed nucleotide in cellular mRNA (Cap 1), promotes the protein expression of specific ISGs that contribute to the antiviral response. Depletion of CMTR1 reduces the IFN-induced protein levels of ISG15, MX1, and IFITM1, without affecting their transcript abundance. However, CMTR1 depletion does not significantly affect the IFN-induced protein or transcript abundance of IFIT1 and IFIT3. Importantly, knockdown of IFIT1, which acts with IFIT3 to inhibit the translation of RNAs lacking Cap 1 2’O methylation, restores protein expression of ISG15, MX1, and IFITM1 in cells depleted of CMTR1. Finally, we found that CMTR1 plays a role in restricting RNA virus replication, likely by ensuring the expression of specific antiviral ISGs. Taken together, these data reveal that CMTR1 is required to establish an antiviral state by ensuring the protein expression of a subset of ISGs during the type I IFN response.ImportanceInduction of an efficient type I IFN response is important to control viral infection. We show that the host 2’O methyltransferase CMTR1 facilitates the protein expression of ISGs in human cells by preventing IFIT1 from inhibiting the translation of these mRNAs lacking cap 2’O methylation. Thus, CMTR1 promotes the IFN-mediated antiviral response.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

Williams

Gokhale

Snider

et al. 2020

Preprint

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“…Interferon-stimulated genes (ISGs) are a large group of genes which have diverse effects on viral infections and mostly act at early stages of virus life-cycle (53). The IFIT proteins are a family of antiviral proteins that form complexes to target viral RNA and inhibit translation (54)(55)(56). Although DENV has been shown to evade interferon responses, induction of ISGs at very early stages before the accumulation of viral proteins that target some of the innate immune components may tip the balance in favor of innate immune responses and block viral RNA replication.…”

Section: Discussionmentioning

confidence: 99%

Zinc Chelation Specifically Inhibits Early Stages of Dengue Virus Replication by Activation of NF-κB and Induction of Antiviral Response in Epithelial Cells

et al. 2019

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Zinc is an essential micronutrient which regulates diverse physiological functions and has been shown to play a crucial role in viral infections. Zinc has a necessary role in the replication of many viruses, however, antiviral action of zinc has also been demonstrated in in vitro infection models most likely through induction of host antiviral responses. Therefore, depending on the host machinery that the virus employs at different stages of infection, zinc may either facilitate, or inhibit virus infection. In this study, we show that zinc plays divergent roles in rotavirus and dengue virus infections in epithelial cells. Dengue virus infection did not perturb the epithelial barrier functions despite the release of virus from the basolateral surface whereas rotavirus infection led to disruption of epithelial junctions. In rotavirus infection, zinc supplementation post-infection did not block barrier disruption suggesting that zinc does not affect rotavirus life-cycle or protects epithelial barriers post-infection suggesting the involvement of cellular pathways in the beneficial effect of zinc supplementation in enteric infections. Zinc depletion by N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN) inhibited dengue virus and Japanese encephalitis virus (JEV) infection but had no effect on rotavirus. Time-of-addition experiments suggested that zinc chelation affected both early and late stages of dengue virus infectious cycle and zinc chelation abrogated dengue virus RNA replication. We show that transient zinc chelation induces ER stress and antiviral response by activating NF-kappaB leading to induction of interferon signaling. These results suggest that modulation of zinc homeostasis during virus infection could be a component of host antiviral response and altering zinc homeostasis may act as a potent antiviral strategy against flaviviruses.

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“…We also show here that the G5-TPR alone does not interact with RNA, irrespectively of whether it consisted of single or double stranded molecules, short hairpins, long stem-loops, or DNA ( Figure 3). This result establishes a main difference with proteins carrying TPR domains involved in RNA-dependent pathways or in direct RNA-binding (Abbas et al, 2013;Grotwinkel et al, 2014;Johnson et al, 2018;Katibah et al, 2013;Yang et al, 2012;Zhou et al, 2018). The high sequence conservation of the TPR-like domain strongly suggests that the dimerization module of Gemin5 plays a fundamental role for the architecture and activity of the protein.…”

Section: Discussionmentioning

confidence: 83%

A novel dimerization module in Gemin5 is critical for protein recruitment and translation control

Moreno-Morcillo

Francisco‐Velilla

Embarc-Buh

et al. 2019

Preprint

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The versatile multifunctional protein Gemin5 is involved in small nuclear ribonucleoproteins (snRNPs) assembly, ribosome binding, and translation control through distinct domains located at the protein ends. However, the structure and function of the central moiety of Gemin5 remained unknown. Here, we solved the crystal structure of an extended tetratricopeptide (TPR)-like domain in the middle region of Gemin5, demonstrating that it self-assembles into a canoe-shaped dimer. Mass spectrometry analysis shows that this dimerization module is functional in living cells and drives the interaction between p85, a viral-induced Gemin5 cleavage fragment, and the full-length Gemin5. In contrast, disruption of the dimerization surface by a point mutation in the TPR-like domain prevents this interaction and abrogates the translation enhancement induced by p85. The structural characterization of this unprecedented dimerization domain provides the mechanistic basis for a role of the middle region of Gemin5 as a key mediator of protein-protein interactions. KeywordsGemin5 dimerization, tetratricopeptide repeat (TPR), alpha-solenoid, RNA-binding protein (RBP), translation regulation, Gemin5-cleavage product p85, X-ray crystallography, proteinprotein interaction, mass spectrometry, RNA-binding site (RBS).

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Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability

Cited by 97 publications

References 40 publications

The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

Zinc Chelation Specifically Inhibits Early Stages of Dengue Virus Replication by Activation of NF-κB and Induction of Antiviral Response in Epithelial Cells

A novel dimerization module in Gemin5 is critical for protein recruitment and translation control

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