Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

RNA-binding protein isoforms ZAP-S and ZAP-L have distinct antiviral and immune resolution functions

Nature Immunology volume 20, pages 1610–1620 (2019)Cite this article

Subjects

Abstract

The initial response to viral infection is anticipatory, with host antiviral restriction factors and pathogen sensors constantly surveying the cell to rapidly mount an antiviral response through the synthesis and downstream activity of interferons. After pathogen clearance, the host’s ability to resolve this antiviral response and return to homeostasis is critical. Here, we found that isoforms of the RNA-binding protein ZAP functioned as both a direct antiviral restriction factor and an interferon-resolution factor. The short isoform of ZAP bound to and mediated the degradation of several host interferon messenger RNAs, and thus acted as a negative feedback regulator of the interferon response. In contrast, the long isoform of ZAP had antiviral functions and did not regulate interferon. The two isoforms contained identical RNA-targeting domains, but differences in their intracellular localization modulated specificity for host versus viral RNA, which resulted in disparate effects on viral replication during the innate immune response.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: ZAP-S interacts with the 3′-UTR of IFN mRNAs.
Fig. 2: CSTF2-mediated alternative polyadenylation generates ZAP-S.
Fig. 3: ZAP-deficient cells have a higher and more prolonged IFN response.
Fig. 4: ZAP-S and ZAP-L localize to different subcellular compartments.
Fig. 5: ZAP-L targets alphavirus RNA at viral replication sites.
Fig. 6: ZAP-S, but not ZAP-L, suppresses IFN.
Fig. 7: Localization of ZAP isoforms determines binding of IFN mRNA.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Schoggins, J. W. et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472, 481–485 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Harris, R. S. & Dudley, J. P. APOBECs and virus restriction. Virology 479-480, 131–145 (2015).

    Article  CAS  PubMed  Google Scholar 

  3. Haller, O., Staeheli, P., Schwemmle, M. & Kochs, G. Mx GTPases: dynamin-like antiviral machines of innate immunity. Trends Microbiol. 23, 154–163 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Diamond, M. S. & Farzan, M. The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat. Rev. Immunol. 13, 46–57 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Jarret, A. et al. Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling. Nat. Med. 22, 1475–1481 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. McFarland, A. P. et al. The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs. Nat. Immunol. 15, 72–79 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Savan, R. Post-transcriptional regulation of interferons and their signaling pathways. J. Interferon Cytokine Res. 34, 318–329 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schwerk, J. & Savan, R. Translating the untranslated region. J. Immunol. 195, 2963–2971 (2015).

    Article  CAS  PubMed  Google Scholar 

  9. Bick, M. J. et al. Expression of the zinc-finger antiviral protein inhibits alphavirus replication. J. Virol. 77, 11555–11562 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gao, G., Guo, X. & Goff, S. P. Inhibition of retroviral RNA production by ZAP, a CCCH-type zinc finger protein. Science 297, 1703–1706 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Muller, S. et al. Inhibition of filovirus replication by the zinc finger antiviral protein. J. Virol. 81, 2391–2400 (2007).

    Article  PubMed  CAS  Google Scholar 

  12. Zhu, Y. et al. Zinc-finger antiviral protein inhibits HIV-1 infection by selectively targeting multiply spliced viral mRNAs for degradation. Proc. Natl Acad. Sci. USA 108, 15834–15839 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guo, X., Carroll, J. W., Macdonald, M. R., Goff, S. P. & Gao, G. The zinc finger antiviral protein directly binds to specific viral mRNAs through the CCCH zinc finger motifs. J. Virol. 78, 12781–12787 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Guo, X., Ma, J., Sun, J. & Gao, G. The zinc-finger antiviral protein recruits the RNA processing exosome to degrade the target mRNA. Proc. Natl Acad. Sci. USA 104, 151–156 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Kerns, J. A., Emerman, M. & Malik, H. S. Positive selection and increased antiviral activity associated with the PARP-containing isoform of human zinc-finger antiviral protein. PLoS Genet. 4, e21 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Vyas, S., Chesarone-Cataldo, M., Todorova, T., Huang, Y. H. & Chang, P. A systematic analysis of the PARP protein family identifies new functions critical for cell physiology. Nat. Commun. 4, 2240 (2013).

    Article  PubMed  CAS  Google Scholar 

  17. Hayakawa, S. et al. ZAPS is a potent stimulator of signaling mediated by the RNA helicase RIG-I during antiviral responses. Nat. Immunol. 12, 37–44 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Ryman, K. D. et al. Sindbis virus translation is inhibited by a PKR/RNase l-independent effector induced by alpha/beta interferon priming of dendritic cells. J. Virol. 79, 1487–1499 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang, N. et al. Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-κB-independent. J. Biol. Chem. 285, 6080–6090 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Takagaki, Y., Seipelt, R. L., Peterson, M. L. & Manley, J. L. The polyadenylation factor CstF-64 regulates alternative processing of IgM heavy chain pre-mRNA during B cell differentiation. Cell 87, 941–952 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Chuvpilo, S. et al. Alternative polyadenylation events contribute to the induction of NF-ATc in effector T cells. Immunity 10, 261–269 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Shell, S. A., Hesse, C., Morris, S. M. Jr. & Milcarek, C. Elevated levels of the 64-kDa cleavage stimulatory factor (CstF-64) in lipopolysaccharide-stimulated macrophages influence gene expression and induce alternative poly(A) site selection. J. Biol. Chem. 280, 39950–39961 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Lee, H. et al. Zinc-finger antiviral protein mediates retinoic acid inducible gene I-like receptor-independent antiviral response to murine leukemia virus. Proc. Natl Acad. Sci. USA 110, 12379–12384 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Charron, G., Li, M. M., MacDonald, M. R. & Hang, H. C. Prenylome profiling reveals S-farnesylation is crucial for membrane targeting and antiviral activity of ZAP long-isoform. Proc. Natl Acad. Sci. USA 110, 11085–11090 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang, M. & Casey, P. J. Protein prenylation: unique fats make their mark on biology. Nat. Rev. Mol. Cell Biol. 17, 110–122 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Gustafsson, M. G. Surpassing the lateral resolution limit by a factor of two using structured illumination microscopy. J. Microsc. 198, 82–87 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Zhang, Y., Burke, C. W., Ryman, K. D. & Klimstra, W. B. Identification and characterization of interferon-induced proteins that inhibit alphavirus replication. J. Virol. 81, 11246–11255 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kujala, P. et al. Biogenesis of the Semliki Forest virus RNA replication complex. J. Virol. 75, 3873–3884 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. DiCiommo, D. P. & Bremner, R. Rapid, high level protein production using DNA-based Semliki Forest virus vectors. J. Biol. Chem. 273, 18060–18066 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Chiu, H. P. et al. Inhibition of Japanese encephalitis virus infection by the host zinc-finger antiviral protein. PLoS Pathog. 14, e1007166 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Zhu, Y. & Gao, G. ZAP-mediated mRNA degradation. RNA Biol. 5, 65–67 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Zhu, Y., Wang, X., Goff, S. P. & Gao, G. Translational repression precedes and is required for ZAP-mediated mRNA decay. EMBO J. 31, 4236–4246 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rosengren, A. T., Nyman, T. A., Syyrakki, S., Matikainen, S. & Lahesmaa, R. Proteomic and transcriptomic characterization of interferon-α-induced human primary T helper cells. Proteomics 5, 371–379 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Huang, Z., Wang, X. & Gao, G. Analyses of SELEX-derived ZAP-binding RNA aptamers suggest that the binding specificity is determined by both structure and sequence of the RNA. Protein Cell 1, 752–759 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Takata, M. A. et al. CG dinucleotide suppression enables antiviral defence targeting non-self RNA. Nature 550, 124–127 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chen, S. et al. Structure of N-terminal domain of ZAP indicates how a zinc-finger protein recognizes complex RNA. Nat. Struct. Mol. Biol. 19, 430–435 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Glasker, S., Toller, M. & Kummerer, B. M. The alternate triad motif of the poly(ADP-ribose) polymerase-like domain of the human zinc finger antiviral protein is essential for its antiviral activity. J. Gen. Virol. 95, 816–822 (2014).

    Article  PubMed  CAS  Google Scholar 

  38. Liu, C. H., Zhou, L., Chen, G. & Krug, R. M. Battle between influenza A virus and a newly identified antiviral activity of the PARP-containing ZAPL protein. Proc. Natl Acad. Sci. USA 112, 14048–14053 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang, X. L. et al. Sindbis virus can exploit a host antiviral protein to evade immune surveillance. J. Virol. 90, 10247–10258 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Saito, T., Owen, D. M., Jiang, F., Marcotrigiano, J. & Gale, M. Jr. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454, 523–527 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Urban, T. J. et al. IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. Hepatology 52, 1888–1896 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Friedman, J. R., Webster, B. M., Mastronarde, D. N., Verhey, K. J. & Voeltz, G. K. ER sliding dynamics and ER-mitochondrial contacts occur on acetylated microtubules. J. Cell Biol. 190, 363–375 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rowland, A. A., Chitwood, P. J., Phillips, M. J. & Voeltz, G. K. ER contact sites define the position and timing of endosome fission. Cell 159, 1027–1041 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Olenych, S. G., Claxton, N. S., Ottenberg, G. K. & Davidson, M. W. The fluorescent protein color palette. Curr. Protoc. Cell Biol. 33, 21.5.25 (2006).

    Article  Google Scholar 

  45. Vogt, D. A. & Ott, M. Membrane flotation assay. Bio Protoc. 5, e1435 (2015).

    Article  PubMed  Google Scholar 

  46. Boritz, E., Gerlach, J., Johnson, J. E. & Rose, J. K. Replication-competent rhabdoviruses with human immunodeficiency virus type 1 coats and green fluorescent protein: entry by a pH-independent pathway. J. Virol. 73, 6937–6945 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This project was funded by National Institutes of Health grants (nos. AI108765 and AI135437 to R.S.; no. AI119017 to M.D.D.; and nos. AI104002, AI118916 and AI127463 to M.G.); the Pew Biomedical Scholars program (no. 32011 to M.D.D.); a Research Fellowship from the German Research Foundation (no. SCHW 1881/1-1 to J.S.); T32 training grants (nos. AI106677 and GM007270 to F.W.S.); and T32 training grant (no. GM007240 to A.P.R.). This work was supported in part by the UW Proteomics Resource (UWPR95794). We thank P. von Haller and J. Eng (UW Proteomics Resource) for expert technical assistance with mass spectrometry. We are thankful for the support of W. P. Chang (UW Biology Imaging Facility) for help with super-resolution microscopy. We thank M. A. Davis (UW Immunology) for help with confocal laser scanning microscopy, D. B. Stetson and K. Burleigh (UW Immunology) for providing the IRF3 CRISPR construct, S. N. Sarkar (University of Pittsburgh) for providing STAT1 KO PH5CH8 cells and members of the Savan, Daugherty and Gale laboratories for helpful discussions.

Author information

Author notes

  1. These authors contributed equally: Johannes Schwerk, Frank W. Soveg.

Authors and Affiliations

  1. Department of Immunology, School of Medicine, University of Washington, Seattle, WA, USA

    Johannes Schwerk, Frank W. Soveg, Kerri R. Thomas, Lauren D. Hatfield, Snehal Ozarkar, Adriana Forero, Alison M. Kell, Justin A. Roby, Lomon So, Michael Gale Jr. & Ram Savan

  2. Section of Molecular Biology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA

    Andrew P. Ryan & Matthew D. Daugherty

  3. Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA

    Lomon So

  4. Department of Microbiology, School of Medicine, University of Washington, Seattle, WA, USA

    Jennifer L. Hyde

  5. Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA, USA

    Michael Gale Jr. & Ram Savan

Authors
  1. Johannes Schwerk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frank W. Soveg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew P. Ryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kerri R. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lauren D. Hatfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Snehal Ozarkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adriana Forero
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alison M. Kell
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Justin A. Roby
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lomon So
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jennifer L. Hyde
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michael Gale Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Matthew D. Daugherty
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ram Savan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.S., F.W.S., M.G., M.D.D. and R.S. designed the study. R.S. directed the study. J.S., F.W.S., A.P.R., K.R.T., L.D.H., S.O., A.F., A.M.K., J.A.R., L.S. and J.L.H. performed experiments and analyzed the data. J.S., M.D.D. and R.S. wrote the manuscript.

Corresponding authors

Correspondence to Matthew D. Daugherty or Ram Savan.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Ioana Visan was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Integrated supplementary information

Supplementary Figure 1 ZAP-S interacts with the 3′UTR of IFN mRNAs.

(a) ZAP RNA-IP performed in Huh7 ZAP KO cells under UV crosslinking conditions after expression of FLAG-tagged ZAP-S, FLAG-tagged ZAP-L and FLAG-empty vector (EV) control, and stimulation with 0.2 µg/ml RIG-I ligand for 24 h. (b) RNA-IP of endogenous ZAP performed in Huh7 WT and IFNAR1 KO cells after stimulation with 0.5 µg/ml RIG-I ligand for 24 h. Representative experiments of (a) two and (b) three independently performed experiments with similar results are shown.

Supplementary Figure 2 ZAP-deficient cells have a higher and more prolonged IFN response.

(a) Western blot of Huh7 ZAP KO cell pools generated by CRISPR-Cas9 technology using two different guide RNAs. (b) ZAP mRNA expression in ZAP KO cell pools. (c) IFNB and IFNL3 mRNA expression in ZAP KO cell pools compared to WT cells and a single-cell sub-clone after stimulation with RIG-I ligand for 24 h. (a-c) Representative experiments with replicates (n = 3) of two independently performed experiments with similar results are shown. Bars show mean ± SD. (d) Sequencing chromatogram of the CRISPR target region in exon 1 of the human ZAP (ZC3HAV1) gene. Four bacterial clones were sequenced showing the same del C deletion. (e) Alignment of WT and CRISPR targeted ZAP polypeptide sequence (amino acid residue 1-200). The ΔC base pair deletion results in a premature stop codon at amino acid residue 121 (exon 2). (f) Polysome profiling of HPRT and IFNB mRNA after overexpression of ZAP-S (green), ZAP-L (blue), or empty vector (EV, black) control in Huh7 ZAP KO cells and stimulation of the cells with 0.25 µg/ml RIG-I ligand for 18 h. A representative of two independent experiments with similar results is shown. Data were analyzed using one-way ANOVA with Tukey’s post-test. *P < 0.01; **P < 0.001; ns, not significant.

Supplementary Figure 3 ZAP-S and ZAP-L localize to different subcellular compartments.

(a) Immunofluorescence staining of endogenous ZAP in Huh7 WT and ZAP KO cells. The scale bar represents 20 µm. (b) Subcellular fractionation of ZAP WT and CaaX mutant isoforms after expression in Huh7 ZAP KO cells. For (a, b) representative micrographs and Western blots of three independent experiments with similar results are shown.

Supplementary Figure 4 ZAP-L co-localizes with endolysosomes.

(a, b) Confocal immunofluorescence microscopy of ZAP and (a) Rab5 or (b) Rab7 after co-expression of mCherry-Rab5 or mCherry-Rab7 and tag-less ZAP-S, ZAP-L, or their CaaX mutants in Huh7 ZAP KO cells. The scale bar represents 5 µm. Representative micrographs of three independent experiments with similar results are shown.

Supplementary Figure 5 ZAP-L does not co-localize with the endoplasmic reticulum, peroxisomes or mitochondria.

(a) Confocal immunofluorescence microscopy of ZAP and the endoplasmic reticulum marker Sec61β. Representative micrographs of three independent experiments with similar results are shown. (b) Quantification of co-localization of ZAP-positive and Sec61β-positive pixels. The correlation coefficients (Pearson’s r) of 10 cells were analyzed using the Fiji Coloc 2 plugin. Error bars show mean ± SD. (c) Membrane flotation assay and sedimentation of ZAP-L, ZAP-S, and the endoplasmic reticulum marker calnexin in Huh7 WT cells treated with or without 0.25 µg/ml RIG-I ligand for 24 h. A representative Western blot of two independently performed experiments with similar results is shown. (d, e) Confocal immunofluorescence microscopy of ZAP and (d) the peroxisomal marker PTS1 and (e) the mitochondrial marker COX8 after co-expression of mCherry-tagged PTS1 and COX8 together with tag-less ZAP-L. The scale bar represents 5 µm. (d, e) Representative micrographs of three independent experiments with similar results are shown.

Supplementary Figure 6 ZAP-L targets alphavirus RNA at viral replication sites.

(a) Confocal immunofluorescence microscopy of endogenous ZAP, SINV dsRNA, and E-cadherin in Huh7 WT cells upon infection with SINV Toto (MOI = 1; 6 h post-infection). The scale bar represents 5 µm. (b) Confocal immunofluorescence microscopy of endogenous ZAP, SINV dsRNA, and G3BP1 in Huh7 WT cells upon infection with SINV Toto (MOI = 1; 6 h post-infection). The scale bar represents 5 µm. (a, b) Representative micrographs of three independent experiments with similar results are shown. (c) Replication activity of a Semliki Forest virus (SFV) luciferase replicon in doxycycline-inducible HEK 293 T cells expressing ZAP-S WT, ZAP-L WT, or their respective CaaX motif mutants. A representative experiment with replicates (n = 3) of three independently performed experiments with similar results is shown. Symbols show mean ± SD.

Supplementary Figure 7 ZAP-S, but not ZAP-L, suppresses IFN.

(a) Western blot of ZAP isoform expression and (b) IFNB and IFNL3 mRNA expression in HEK 293 cells after isoform-specific knockdown of ZAP and stimulation with 1 µg/ml RIG-I ligand for 30 h. (a, b) A representative experiment with replicates (n = 3) of three independently performed experiments with similar results is shown. Bars show mean ± SD. (c) IL6 and TNFA mRNA expression in Huh7 cells upon isoform-specific knockdown of ZAP and stimulation with 0.5 µg/ml RIG-I ligand for 42 h. A representative experiment with replicates (n = 3) of two independently performed experiments with similar results is shown. Bars show mean ± SD. (d) ZAP RNA-IP performed in Huh7 ZAP KO cells after expression of FLAG-tagged ZAP-S, FLAG-tagged ZAP-L and FLAG-empty vector (EV) control, and stimulation with 0.2 µg/ml RIG-I ligand for 24 h. A representative experiment of two independently performed experiments with similar results is shown. (e) Expression of IFNB and IFNL3 mRNA and (f) Western blot of IRF1 protein expression in Huh7 WT and ZAP KO cells 48 h after overexpression of IRF1. (e, f) A representative experiment with replicates (n = 3) of three independently performed experiments with similar results is shown. Bars show mean ± SD. Data were analyzed using (b, c) one-way ANOVA with Tukey’s post-test or (e) unpaired two-tailed Student’s t-test. *P < 0.05; **P < 0.01; ***P < 0.001; ns, not significant.

Supplementary Figure 8 Model of ZAP-mediated post-transcriptional regulation during innate antiviral immunity.

Constitutively expressed ZAP-L localizes to endolysosomes and sites of Sindbis virus replication at the plasma membrane to target viral RNA (vRNA) and inhibit viral replication. Escaping vRNA triggers expression and secretion of type I and III IFNs, which engage and signal through the IFN receptors. This induces CSTF2-mediated alternative polyadenylation and alternative last exon usage of ZC3HAV1 and expression of ZAP-S, which then binds to IFN mRNA in the cytoplasm to mediate resolution of the antiviral innate immune response.

Supplementary information

Supplementary Information

Supplementary Figs. 1–8 and Tables 1–3.

Reporting Summary

Source data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schwerk, J., Soveg, F.W., Ryan, A.P. et al. RNA-binding protein isoforms ZAP-S and ZAP-L have distinct antiviral and immune resolution functions. Nat Immunol 20, 1610–1620 (2019). https://doi.org/10.1038/s41590-019-0527-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-019-0527-6

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing