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A balancing act between IFITM3 and IRF3

Cellular & Molecular Immunology volume 15, pages 873–874 (2018)Cite this article

IFITM3 is particularly well characterized as a restriction factor able to limit influenza virus infections, and is responsible for a significant portion of the antiviral action of type I IFNs against influenza virus in cells.6,7 As such, IFITM3 knockout mice succumb to sublethal doses of influenza virus and exhibit increased lung pathology compared to control mice.8,9 Further, homozygosity of a single nucleotide polymorphism in the human IFITM3 gene, rs-12252-C, has been associated with increased morbidity and mortality in individuals hospitalized from infections with the 2009 pandemic H1N1 influenza A virus or with an emergent H7N9 virus.8,10,11 This polymorphism is thought to result in an alternatively spliced IFITM3 transcript coding for a truncated and mislocalized protein, though evidence for a truncated variant of IFITM3 is lacking.8 Nonetheless, IFITM3 is well established as a critical component of the innate anti-influenza virus immune response in mice and humans.1

Although IFITM3 is appreciated primarily as an antiviral protein able to block virus membrane fusion, we, and others, have also noted the ability of IFITM3 to induce autophagosome formation in cells as indicated by LC3 lipidation and puncta formation.2,3 We previously demonstrated that antiviral activity of IFITM3 is independent of the canonical ATG5-dependent autophagy pathway, thus decoupling autophagy induction by IFITM3 from its antiviral activity.3 This suggested that, in addition to directly inhibiting viruses, IFITM3 may also play a role in regulating autophagy, though the biological relevance of such a role has been difficult to identify. New work by Jiang et al. 12 published in this edition of Cellular and Molecular Immunology, identified a novel function for IFITM3 in inhibiting IFN-β induction by promoting degradation of IFN regulatory factor 3 (IRF3), a critical transcription factor necessary for activating IFN-β production upon infection. The authors propose that this IRF3 degradation occurs within IFITM3-associated autophagosomes (Figure 1). This work describes the first reported immunoregulatory role for IFITM3 in the type I IFN pathway.

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Figure 1

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Acknowledgements

TMM is supported by a Gilliam Graduate Fellowship from the Howard Hughes Medical Institute. JSY is supported by NIH Grant AI130110.

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  1. Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, Columbus, 43210, OH, USA

    Temet M McMichael, Mahesh Chemudupati & Jacob S Yount

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  1. Temet M McMichael
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Correspondence to Jacob S Yount.

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McMichael, T.M., Chemudupati, M. & Yount, J.S. A balancing act between IFITM3 and IRF3. Cell Mol Immunol 15, 873–874 (2018). https://doi.org/10.1038/cmi.2017.18

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