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Basal expression of interferon regulatory factor 1 drives intrinsic hepatocyte resistance to multiple RNA viruses

Nature Microbiology volume 4, pages 1096–1104 (2019)Cite this article

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Abstract

Current models of cell-intrinsic immunity to RNA viruses centre on virus-triggered inducible antiviral responses initiated by RIG-I-like receptors or Toll-like receptors that sense pathogen-associated molecular patterns, and signal downstream through interferon regulatory factors (IRFs), transcription factors that induce synthesis of type I and type III interferons1. RNA viruses have evolved sophisticated strategies to disrupt these signalling pathways and evade elimination by cells, attesting to their importance2. Less attention has been paid to how IRFs maintain basal levels of protection against viruses. Here, we depleted antiviral factors linked to RIG-I-like receptor and Toll-like receptor signalling to map critical host pathways restricting positive-strand RNA virus replication in immortalized hepatocytes and identified an unexpected role for IRF1. We show that constitutively expressed IRF1 acts independently of mitochondrial antiviral signalling (MAVS) protein, IRF3 and signal transducer and activator of transcription 1 (STAT1)-dependent signalling to provide intrinsic antiviral protection in actinomycin D-treated cells. IRF1 localizes to the nucleus, where it maintains the basal transcription of a suite of antiviral genes that protect against multiple pathogenic RNA viruses, including hepatitis A and C viruses, dengue virus and Zika virus. Our findings reveal an unappreciated layer of hepatocyte-intrinsic immunity to these positive-strand RNA viruses and identify previously unrecognized antiviral effector genes.

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Fig. 1: IRF1 restricts RNA virus infections in hepatocytes.
Fig. 2: IRF1 constitutively activates basal transcription of PRDIII-I- and ISRE-dependent antiviral genes.
Fig. 3: Shared and distinct antiviral activities of IRF1 effector genes identified by high-throughput RNA-seq.
Fig. 4: IRF1-regulated RARRES3 acyl transferase restricts HAV replication by downregulating mTOR.

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Data availability

All data supporting the findings of this study are available within the paper and in its Supplementary Information. The RNA-seq data have been deposited with the Gene Expression Omnibus (GSE114916).

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Acknowledgements

The authors thank C.M. Rice, S. Inoue and N. Kato for the reagents, M. Soloway for the bioinformatics support, M. Chua for technical assistance and H. Dansako, B.B. Queliconi and W.J. Zuercher for helpful discussions. This work was supported in part by the Japan Society for the Promotion of Science (JSPS KAKENHI) (grant nos. JP16H07462 and JP17H05070 to D.Y., grant no. JP18K05987 to A.H-Y., grant no. JP17K08870 and JP15K19109 to T.H.), Japan Agency for Medical Research and Development (grant no. JP18jk0210014 to A.H.-Y., grant no. JP18fk0108035 to T.H. and grant no. JP16fk0210108 to M.K.) and National Institutes of Health grant no. R01-AI103083 and U19-AI109965 to S.M.L. and grant no. R01-AI131685 to S.M.L. and J.K.W.

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Authors and Affiliations

  1. UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

    Daisuke Yamane, Hui Feng, Efraín E. Rivera-Serrano, Sara R. Selitsky, Asuka Hirai-Yuki, Anshuman Das, Kevin L. McKnight, Lucinda Hensley, William Lovell, Olga González-López, Eliane Wauthier, Tsunekazu Oikawa, Lola M. Reid, Praveen Sethupathy, Jason K. Whitmire & Stanley M. Lemon

  2. Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Daisuke Yamane, Hui Feng, Efraín E. Rivera-Serrano, Asuka Hirai-Yuki, Anshuman Das, Kevin L. McKnight, Lucinda Hensley, William Lovell, Olga González-López & Stanley M. Lemon

  3. Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Daisuke Yamane, Hui Feng, Efraín E. Rivera-Serrano, Asuka Hirai-Yuki, Anshuman Das, Kevin L. McKnight, Lucinda Hensley, William Lovell, Olga González-López & Stanley M. Lemon

  4. Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan

    Daisuke Yamane, Takayuki Hishiki & Michinori Kohara

  5. Division of Experimental Animal Research, National Institute of Infectious Diseases, Tokyo, Japan

    Asuka Hirai-Yuki

  6. Department of Microbiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Ichiro Misumi & Jason K. Whitmire

  7. Department of Immunology and Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Ichiro Misumi & Jason K. Whitmire

  8. Department of Virology II, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan

    Ryosuke Suzuki & Mami Matsuda

  9. Research Center for Biosignaling, Akita University,, Akita, Japan

    Hiroki Nakanishi

  10. Lipidome Lab Co., Ltd,, Akita, Japan

    Takayo Ohto-Nakanishi

  11. Department of Cell Biology and Physiology Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Eliane Wauthier, Tsunekazu Oikawa & Lola M. Reid

  12. Division of Gastroenterology and Hepatology, Depertment of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan

    Tsunekazu Oikawa

  13. Department of Virology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan

    Kouichi Morita

  14. Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA

    Praveen Sethupathy

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  1. Daisuke Yamane
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Contributions

D.Y. and S.M.L. conceived the study and wrote the manuscript. D.Y., H.F., E.E.R.-S., A.H.-Y., K.L.M., I.M., L.H., W.L. and O.G.-L. performed the experiments. S.R.S. and P.S. performed the bioinformatics analysis. H.N. and T.O.-N. performed the lipidomics analysis. A.D., R.S., M.M., T.H., E.W., T.O., K.M., L.M.R., M.K. and J.K.W. provided the research materials and supervised the experiments. All authors commented on the manuscript.

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Correspondence to Daisuke Yamane or Stanley M. Lemon.

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Yamane, D., Feng, H., Rivera-Serrano, E.E. et al. Basal expression of interferon regulatory factor 1 drives intrinsic hepatocyte resistance to multiple RNA viruses. Nat Microbiol 4, 1096–1104 (2019). https://doi.org/10.1038/s41564-019-0425-6

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