The emerging roles of IFIT3 in antiviral innate immunity and cellular biology

Zhang, Wentao; Li, Yanling; Xin, Shuyu; Yang, Li; Jiang, Mingjuan; Xin, Yujie; Wang, Yiwei; Cao, Pengfei; Zhang, Senmiao; Yang, Yang; Lu, Jianhong

doi:10.1002/jmv.28259

Cited by 22 publications

(21 citation statements)

References 85 publications

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“…These data indicate that over a wide range of IFN doses, ZAP, IFIT3, and IFIT1 together comprise an outsized proportion of the total IFN-mediated suppression of VEEV-GFP. ZAP, IFIT3, and IFIT1 have been shown to exhibit broad antiviral activity towards diverse viruses (Andrejeva et al, 2013;Bick et al, 2003;Chikhalya et al, 2021;Fensterl & Sen, 2015;Gao et al, 2002;Gonzalez-Perez et al, 2021;Griffante et al, 2021;Hyde et al, 2014;Johnson et al, 2018;Pichlmair et al, 2011;Reynaud et al, 2015;Schmeisser et al, 2010;Zhang et al, 2022). We therefore used gene silencing to determine the contribution of ZAP, IFIT3, and IFIT1 to the antiviral activity of IFN towards other IFN-sensitive viruses.…”

Section: Resultsmentioning

confidence: 99%

Interferon inhibits a model RNA virus via a limited set of inducible effector genes

McDougal

Maria

Ohlson

et al. 2023

Preprint

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Interferons control viral infection by inducing the expression of antiviral effector proteins encoded by interferon-stimulated genes (ISGs). The field has mostly focused on identifying individual antiviral ISG effectors and defining their mechanisms of action. However, fundamental gaps in knowledge about the interferon response remain. For example, it is not known how many ISGs are required to protect cells from a particular virus, though it is theorized that numerous ISGs act in concert to achieve viral inhibition. Here, we used CRISPR-based loss-of-function screens to identify a markedly limited set of ISGs that confer interferon-mediated suppression of a model alphavirus, Venezuelan equine encephalitis virus (VEEV). We show via combinatorial gene targeting that three antiviral effectors, ZAP, IFIT3, and IFIT1, together constitute the majority of interferon-mediated restriction of VEEV, while accounting for less than 0.5% of the interferon-induced transcriptome. Together, our data suggests a refined model of the antiviral interferon response in which a small subset of 'dominant' ISGs may confer the bulk of the inhibition of a given virus.

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Section: Resultsmentioning

confidence: 99%

Interferon inhibits a model RNA virus via a limited set of inducible effector genes

McDougal

Maria

Ohlson

et al. 2023

Preprint

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“…IFNB1 and other type I interferons activate the JAK-STAT cascade that induces interferon-stimulated genes such as IFIT2 (also called ISG54), IFIT3 (ISG60), and ISG15. IFIT2 (selected in C) and IFIT3 (selected in R) encode cytoplasmic proteins that restrict replication of corona-and many other viruses by sensing viral mRNAs and inhibiting their translation [76][77][78][79] . ISG15 is an antiviral protein that lacks a key Cysteine residue in rhinolophid and hipposiderid bats which is required for homodimer formation (investigated in detail below).…”

Section: Relevant Immune-related Changes In Batsmentioning

confidence: 99%

Reference-quality bat genomes illuminate adaptations to viral tolerance and disease resistance

Hiller

Morales

Ahmed

et al. 2023

Preprint

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Bats carry viruses that can cause severe disease in other mammals. Asymptomatic infections in bats suggest limited tissue-damaging inflammation and immunopathology. To investigate the genomic basis of disease resistance, the Bat1K project generated reference-quality genomes of ten bat species. A systematic analysis showed that signatures of selection in immune genes are more prevalent in bats compared with other mammals. We found an excess of immune gene adaptations in the ancestral Chiroptera and many descending bat lineages, highlighting viral entry and detection factors, and regulators of antiviral and inflammatory responses. ISG15, an antiviral gene contributing to hyperinflammation during COVID-19, exhibits a deletion of a cysteine, required for homodimer formation, in rhinolophid and hipposiderid bats. Cellular infection experiments showed enhanced intracellular protein conjugation of bat ISG15 and lack of secretion into extracellular space, where human ISG15 stimulates inflammation. Our work highlights molecular mechanisms contributing to viral tolerance and disease resistance in bats.

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“…Regarding the known role of IFIT3 in antiviral innate immunity, 20 to further investigate the mechanism of IFIT3 in inhibiting EBV lytic replication, we examined the effect of IFIT3 on a subset of ISGs.…”

Section: Ifit3 Increases the Transcription Of Isgs In Ebv Lytic Repli...mentioning

confidence: 99%

“…18,19 The IFN-induced protein with tetratricopeptide repeats 3 (IFIT3) is a member of the IFIT family and one of the important ISGs. 20 Without external stimuli, most cells do not express or poorly express IFIT3. A mountain of studies has shown that a variety of RNA or DNA viruses can induce the expression of IFIT3, including rabies virus (RV), 21 BK polyomavirus, 22 hepatitis C virus (HCV) 23,24 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).…”

Section: Introductionmentioning

confidence: 99%

IFIT3 inhibits Epstein‐Barr virus reactivation via upregulating innate immunity

Zhang,

Jiang,

Liao

et al. 2023

Journal of Medical Virology

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Epstein‐Barr virus (EBV), a member of the γ‐herpesvirus family, can establish latent infection in B lymphocytes and certain epithelial cells after primary infection. Under certain circumstances, EBV can enter into lytic replication. However, the regulation of EBV latent‐lytic infection remains largely unclear. The important immune molecule, interferon‐induced protein with tetratricopeptide repeats 3 (IFIT3), was upregulated in EBV latently infected cells. When the lytic replication of EBV was induced, the expression of IFIT3 was further increased. In turn, IFIT3 overexpression dramatically inhibited the lytic replication of EBV, while IFIT3 knockdown facilitated EBV lytic replication. Moreover, upon the lytic induction, the ectopic IFIT3 expression promoted the activation of the interferon (IFN) pathway, including the production of IFN‐stimulated genes (ISGs), IFNB1, and the phosphorylation of IFN‐regulatory factor 3 (IRF3). In contrast, the depletion of IFIT3 led to decreased ISGs and IFNB1 expression. Mechanically, IFIT3 inhibited EBV lytic replication through IFN signaling. This study revealed that the host innate immune‐related factor IFIT3 played an important role in regulating EBV latent‐lytic homeostasis. The results implied that EBV has evolved well to utilize host factors to maintain latent infection.

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The emerging roles of IFIT3 in antiviral innate immunity and cellular biology

Cited by 22 publications

References 85 publications

Interferon inhibits a model RNA virus via a limited set of inducible effector genes

Interferon inhibits a model RNA virus via a limited set of inducible effector genes

Reference-quality bat genomes illuminate adaptations to viral tolerance and disease resistance

IFIT3 inhibits Epstein‐Barr virus reactivation via upregulating innate immunity

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