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Finding a fairy in the forest: ELF4, a novel and critical element of type I interferon responses

Cellular & Molecular Immunology volume 11, pages 218–220 (2014)Cite this article

Innate immune responses are initiated by invading pathogens through the detection of their evolutionally conserved pathogen-associated molecular patterns. Detection of viral pathogen-associated molecular patterns is carried out by intracellular Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and several other nucleic acid sensors, such as AIM2-like receptors.2 As a result of pathogen-associated molecular pattern-induced activation, PRRs trigger NF-κB-dependent inflammatory cytokine and chemokine responses and the production of type I IFNs through the activation of IRF3 and IRF7.3 Type I IFNs are critical components in the establishment of the antiviral state and the resistance of host cells to viral replication. PRRs use different adaptor proteins to link the downstream signals to the NF-κB and IRF transcription factors. A crucial element in these pathways is mitochondrial MAVS (also known as VISA, Cardif or IPS-1), which is an ancient adaptor protein that couples RLRs to NF-κB and promotes TBK1 and IRF3 signaling (Figure 1). Previous studies have revealed that the ETS family transcription factor ELF4 takes part in various cellular processes, such as tumorigenesis,4 the DNA damage response5 and cell cycle regulation.6 Despite the growing body of research in this field, the exact physiological role of ELF4 remained unknown.

In their article, You et al. demonstrate that ELF4 is a critical factor in the regulation of type I IFN responses and plays a significant role in the antiviral host defense. ELF4 was shown to interact with STING, as demonstrated by coimmunoprecipitation analysis in HeLa cells. The type I IFN-inducing effect of ELF4 was also tested at both the mRNA and protein levels, and it was shown that the overexpression of this ETS protein was able to induce type I IFN secretion in 293T cells. Using another reporter assay, the group also showed that the ability of ELF4 to induce type I IFN production depended on the C-terminal region of the protein, which is responsible for its interaction with STING. Owing to the ability of ELF4 to induce IFN responses, the group then examined the response of ELF4 to viral challenges. These results showed that the expression of the Elf4 gene was increased by both viral challenge (SeV or VSV) and IFN-β stimulation. Furthermore, overexpression of the ELF4 protein led to the inhibition of viral replication, as was shown by immunoblot and plaque-forming assays. These results confirmed that the ETS domain of ELF4 was essential in the establishment of this antiviral activity. To demonstrate the in vivo significance of ELF4 in the antiviral host defense, the sensitivity of Elf4−/− mice to lethal WNV infection was compared to that of wild-type mice. The results showed that the ELF4-deficient mice were significantly more susceptible to virus exposure than their wild-type counterparts. The type I IFN production of macrophages isolated from Elf4−/− mice was also impaired, showing that ELF4 was involved in the induction of IFN production and antiviral immunity against WNV. These findings are consistent with previous reports that showed the importance of ELF4 in antiviral cellular immune responses.6,7 Interestingly, the group also found that ELF4 controls viral replication in vivo by directly regulating the type I IFN response, not through the contribution of natural killer and natural killer T cells or cytotoxic T lymphocytes.

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  1. Department of Immunology, Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary

    Attila Szabo & Eva Rajnavolgyi

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Szabo, A., Rajnavolgyi, E. Finding a fairy in the forest: ELF4, a novel and critical element of type I interferon responses. Cell Mol Immunol 11, 218–220 (2014). https://doi.org/10.1038/cmi.2014.1

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