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


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.

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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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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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).

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