ZAPS is a potent stimulator of signaling mediated by the RNA helicase RIG-I during antiviral responses

Abstract

The poly(ADP-ribose) polymerases (PARPs) participate in many biological and pathological processes. Here we report that the PARP-13 shorter isoform (ZAPS), rather than the full-length protein (ZAP), was selectively induced by 5′-triphosphate–modified RNA (3pRNA) and functioned as a potent stimulator of interferon responses in human cells mediated by the RNA helicase RIG-I. ZAPS associated with RIG-I to promote the oligomerization and ATPase activity of RIG-I, which led to robust activation of IRF3 and NF-κB transcription factors. Disruption of the gene encoding ZAPS resulted in impaired induction of interferon-α (IFN-α), IFN-β and other cytokines after viral infection. These results indicate that ZAPS is a key regulator of RIG-I signaling during the innate antiviral immune response, which suggests its possible use as a therapeutic target for viral control.

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Figure 1: Involvement of PARP-superfamily members in interferon responses to cytosolic nucleic acids.
Figure 2: ZAPS is a potent stimulator of RIG-I-mediated type I interferon responses activated by 3pRNA.
Figure 3: ZAPS activates both the NF-κB and IRF3 transcriptional pathways in a RIG-I- and MAVS-dependent manner.
Figure 4: ZAPS interacts with RIG-I to positively modulate the RIG-I activity.
Figure 5: ZAPS is a key regulator of RIG-I-mediated induction of type I interferons and antiviral innate defense.
Figure 6: Crucial role for ZAPS in the induction of cytokine genes by NDV infection.

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  • 08 December 2010

    In the version of this article initially published online, the affiliation of F. Kashigi, S. Goto and S. Kameoka with the Department of Chemistry, Graduate School of Science, Hokkaido University Sapporo, Japan, was omitted. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank T. Fujita (Kyoto University) for the luciferase reporter plasmids p-55C1BLuc and p-125Luc; J. Miyazaki (Osaka University) for the pCAGGS vector; A. Miyawaki (RIKEN) for the Venus vector; H. Kida (Hokkaido University) for NDV; A. Iwai, H. Higashi and J. Hamada for technical help; M. Yamane for the purification of human primary CD14+ monocytes; and S. Tamura and T. Moriyama for advice on recombinant protein purification. Supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant-in-Aid for Young Scientists (A) to S.H., Young Scientists (S) to A.T.) and Scientific Research in Priority Areas (A.T.), IRYO HOJIN SHADAN JIKOKAI (H. Tanaka & N. Takayanagi) (A.T.), the Astellas Foundation for Research on Metabolic Disorders (A.T.), the Kanae Foundation for the Promotion of Medical Science (A.T.), the Kato Memorial Bioscience Foundation (A.T.) and the Yasuda Medical Foundation (A.T.).

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S.H., S.S., H.Y., T.K., C.K., F.K., S.G., S.K., T.Y., M.K., M.S., J.T., M.A. and M.I. planned studies, did experiments and analyzed data; D.F. and T. Miyazaki contributed to viral infection experiments and helped with data analyses; T. Mizutani and Y.O. did fluorescence microscopy experiments and FRET analysis; and A.T. supervised the project, designed experiments and wrote the manuscript with comments from the coauthors.

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Correspondence to Akinori Takaoka.

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Hayakawa, S., Shiratori, S., Yamato, H. 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). https://doi.org/10.1038/ni.1963

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