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The regulatory factor ELF1 triggers a critical wave of transcription in the antiviral response to type I interferon

By Leon Louis Seifert, Clara Si, Sarah Ballentine, Debjani Saha, Maren de Vries, Guojun Wang, Mohammad Sadic, Aaron Briley, Uwe Schäfer, Hong Moulton, Adolfo Garcia-Sastre, Shashank Tripathi, Brad R. Rosenberg, Meike Dittmann

Posted 14 Feb 2019
bioRxiv DOI: 10.1101/549485

The transcription of interferon-stimulated genes (ISGs) is classically triggered via activation of the JAK-STAT pathway, and together, ISGs raise a multifaceted antiviral barrier. An increasing body of evidence reports the existence of additional, non-canonical pathways and transcription factors that coordinate ISG expression. Detailed knowledge of how heterogenous mechanisms regulate ISG expression is crucial for the rational design of drugs targeting the type I interferon response. Here, we characterize the first ETS transcription factor family member as a regulator of non-canonical ISG expression: E74-like ETS transcription factor 1 (ELF1). Using high-content microscopy to quantify viral infection over time, we found that ELF1, itself an ISG, inhibits eight diverse RNA and DNA viruses uniquely at multi-cycle replication. ELF1 did not regulate expression of type I or II interferons, and ELF1's antiviral effect was not abolished by the absence of STAT1 or by inhibition of JAK phosphorylation. Accordingly, comparative expression analyses by RNAseq revealed that the ELF1 transcriptional program is distinct from, and delayed with respect to, the immediate interferon response. Finally, knockdown experiments demonstrated that ELF1 is a critical component of the antiviral interferon response in vitro and in vivo. Our findings reveal a previously overlooked mechanism of non-canonical ISG regulation that both amplifies and prolongs the initial interferon response by expressing broadly antiviral restriction factors.

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