The ETS transcription factor ELF1 regulates a broadly antiviral program distinct from the type I interferon response

Seifert, Leon Louis; Si, Clara; Saha, Debjani; Sadic, Mohammad; Vries, Maren de; Ballentine, Sarah; Briley, Aaron; Wang, Guojun; Valero-Jimenez, Ana M.; Mohamed, Adil; Schaefer, Uwe; Moulton, Hong M.; García‐Sastre, Adolfo; Tripathi, Shashank; Rosenberg, Brad R.; Dittmann, Meike

doi:10.1371/journal.ppat.1007634

Cited by 58 publications

(66 citation statements)

References 77 publications

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“…Finally, the transcription factor ELF1 was also found to affect viral entry. ELF1 governs a complex transcriptional program of over 300 genes that are largely distinct from those induced by IFN, suggesting that a secondary antiviral transcriptional cascade acts to inhibit SARS-CoV-2 entry, and potentially other stages of the viral life cycle (Seifert et al, 2019).…”

Section: Restriction Of Sars-cov-2 Entrymentioning

confidence: 99%

Functional Landscape of SARS-CoV-2 Cellular Restriction

Martin-Sancho

Lewinski

Pache

et al. 2020

Preprint

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A deficient interferon response to SARS-CoV-2 infection has been implicated as a determinant of severe COVID-19. To identify the molecular effectors that govern interferon control of SARS-CoV-2 infection, we conducted a large-scale gain-of-function analysis that evaluated the impact of human interferon stimulated genes (ISGs) on viral replication. A limited subset of ISGs were found to control viral infection, including endosomal factors that inhibited viral entry, nucleic acid binding proteins that suppressed viral RNA synthesis, and a highly enriched cluster of ER and Golgi-resident ISGs that inhibited viral translation and egress. These included the type II integral membrane protein BST2/tetherin, which was found to impede viral release, and is targeted for immune evasion by SARS-CoV-2 Orf7a protein. Overall, these data define the molecular basis of early innate immune control of viral infection, which will facilitate the understanding of host determinants that impact disease severity and offer potential therapeutic strategies for COVID-19.

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Section: Restriction Of Sars-cov-2 Entrymentioning

confidence: 99%

Functional Landscape of SARS-CoV-2 Cellular Restriction

Martin-Sancho

Lewinski

Pache

et al. 2020

Preprint

Self Cite

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“…While a number of reports have documented non-canonical activation or delayed stimulation of subsets of ISGs during viral infection, the molecular pathways that can control these subsets of ISGs are not well understood (Pulit-Penaloza et al, 2012;Rose et al, 2010). However, a number of studies have identified transcriptional regulators of subsets of ISGs (Froggatt et al, 2019;Perwitasari et al, 2011;Seifert et al, 2019), and the mRNA Cap1 methyltransferase CMTR1 was recently shown to regulate the expression of certain ISGs (Williams et al, 2020). These studies demonstrate the complexity of regulation of expression of ISGs that extends beyond transcriptional induction of ISGs from signaling of the JAK-STAT pathway.…”

Section: Discussionmentioning

confidence: 99%

“…However, our overall understanding of posttranscriptional regulation of ISG expression is still emerging. Additionally, while a number of studies have identified subsets of ISGs that have unique transcriptional regulators, other mechanisms that govern the regulation of subclasses of ISGs have not been well characterized (Froggatt et al, 2019;Perwitasari et al, 2011;Seifert et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Post-Transcriptional Regulation of Antiviral Gene Expression byN6-Methyladenosine

McFadden

McIntyre

Mourelatos

et al. 2020

Preprint

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SummaryType I interferons (IFN) induce hundreds of IFN-stimulated genes (ISGs) in response to viral infection. These ISGs require strict regulation for an efficient and controlled antiviral response, but post-transcriptional controls of these genes have not been well defined. Here, we identify a new role for the RNA base modification N6-methyladenosine (m6A) in the regulation of ISGs. Using ribosome profiling and quantitative mass spectrometry, coupled with m6A-immunoprecipitation and sequencing, we identified a subset of ISGs, including IFITM1, whose translation is enhanced by m6A and the m6A methyltransferase proteins METTL3 and METTL14. We further determined that the m6A reader YTHDF1 increases the expression of IFITM1 in an m6A binding-dependent manner. Importantly, we found that the m6A methyltransferase complex promotes the antiviral activity of type I IFN. Thus, these studies identify m6A as a post-transcriptional control of ISG translation during the type I IFN response for antiviral restriction.

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“…ETV7 is induced as an ISG and is repressive, whereas most ETS transcription factors are activators, including ETS transcription factors recognized to assist in the induction of ISG expression (e.g. ELF1 (25), PU.1 (71)). We also found repeatedly in our work that the reporters and genes impacted by ETV7 contained ETS sites within ISRE sequences ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Interferon responsive factors (IRFs) 1 and 7 are ISGs and transcription factors that activate subsets of ISGs (23,24). Further, recent work has shown that ELF1 (E74-like ETS transcription factor) is induced by IFN and facilitates the expression of a group of genes not otherwise activated by the IFN response (25). Additional regulatory steps for ISGs, post-JAK/STAT signaling, likely exist to allow the cell to fine-tune its antiviral activity for an effective and appropriate response.…”

Section: Introductionmentioning

confidence: 99%

ETV7 limits antiviral gene expression and control of SARS-CoV-2 and influenza viruses

Froggatt

Harding

Heaton

et al. 2019

Preprint

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42The type I interferon (IFN) response is an important component of the innate immune 43 response to viral infection. Precise control of interferon responses is critical, as insufficient 44 levels of interferon-stimulated genes (ISGs) can lead to a failure to restrict viral spread, 45 while excessive ISG activation results in interferon-related pathologies. While both 46 positive and negative regulatory factors can control the magnitude and duration of IFN 47Significance 60Interferons (IFNs) were first described in 1957 and are now known to be critical for 61 restriction of viruses. Still, our understanding of the complex web of interactions that 62 underlie IFN responses remains incomplete. In particular, negative regulation of interferon 63 responses has received disproportionately less study. In this work, we performed a 64 genome-wide overexpression screen for factors capable of suppressing IFN response 65 signaling. We identified a DNA binding transcription factor (ETV7) that, after induction by 66 interferon, acts to suppress a subset of IFN-stimulated genes required for control of 67 influenza viruses. Our work highlights the importance of understanding negative IFN 68 signaling not only with respect to the magnitude and duration of the response, but also 69 the specificity of its antiviral effects. 70

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The ETS transcription factor ELF1 regulates a broadly antiviral program distinct from the type I interferon response

Cited by 58 publications

References 77 publications

Functional Landscape of SARS-CoV-2 Cellular Restriction

Functional Landscape of SARS-CoV-2 Cellular Restriction

Post-Transcriptional Regulation of Antiviral Gene Expression byN6-Methyladenosine

ETV7 limits antiviral gene expression and control of SARS-CoV-2 and influenza viruses

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