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:

SNX8 modulates the innate immune response to RNA viruses by regulating the aggregation of VISA

Cellular & Molecular Immunology volume 17, pages 1126–1135 (2020)Cite this article

Subjects

A Correction to this article was published on 06 May 2021

This article has been updated

Abstract

The mitochondrial virus-induced signaling adaptor (VISA, also called mitochondrial antiviral signaling, MAVS) protein is a central adaptor in the innate immune response to cytosolic viral RNA. Viral infection causes the aggregation of VISA, which is important for its recruitment of downstream signaling components. How VISA aggregation is regulated remains unknown. Here, we found that sorting nexin 8 (SNX8) is a positive regulator of the RNA virus-triggered induction of downstream effector genes and innate immune response. The brains and lungs of Snx8−/− mice infected with RNA viruses exhibited lower serum cytokine levels and higher viral titers than those of wild-type mice, resulting in higher lethality. Mechanistically, viral infection induced the translocation of SNX8 from the cytosol to mitochondria and its increased association with VISA, leading to VISA aggregation, its recruitment of downstream signaling components and the induction of downstream antiviral genes. Our findings suggest that SNX8 is a critical component of the RIG-I-like receptor (RLR)-mediated innate immune response by modulating VISA aggregation and activation.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Change history

References

  1. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).

    Article  CAS  Google Scholar 

  2. Gurtler, C. & Bowie, A. G. Innate immune detection of microbial nucleic acids. Trends Microbiol. 21, 413–420 (2013).

    Article  CAS  Google Scholar 

  3. Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105 (2006).

    Article  CAS  Google Scholar 

  4. Yoneyama, M. & Fujita, T. RNA recognition and signal transduction by RIG-I-like receptors. Immunol. Rev. 227, 54–65 (2009).

    Article  CAS  Google Scholar 

  5. Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5, 730–737 (2004).

    Article  CAS  Google Scholar 

  6. Kawai, T. et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6, 981–988 (2005).

    Article  CAS  Google Scholar 

  7. Meylan, E. et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172 (2005).

    Article  CAS  Google Scholar 

  8. Seth, R. B., Sun, L., Ea, C. K. & Chen, Z. J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122, 669–682 (2005).

    Article  CAS  Google Scholar 

  9. Xu, L. G. et al. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol. Cell 19, 727–740 (2005).

    Article  CAS  Google Scholar 

  10. Hou, F. et al. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146, 448–461 (2011).

    Article  CAS  Google Scholar 

  11. Lei, C. Q. et al. Glycogen synthase kinase 3beta regulates IRF3 transcription factor-mediated antiviral response via activation of the kinase TBK1. Immunity 33, 878–889 (2010).

    Article  CAS  Google Scholar 

  12. Mao, A. P. et al. Virus-triggered ubiquitination of TRAF3/6 by cIAP1/2 is essential for induction of interferon-beta (IFN-beta) and cellular antiviral response. J. Biol. Chem. 285, 9470–9476 (2010).

    Article  CAS  Google Scholar 

  13. McWhirter, S. M., Tenoever, B. R. & Maniatis, T. Connecting mitochondria and innate immunity. Cell 122, 645–647 (2005).

    Article  CAS  Google Scholar 

  14. Wang, Y. Y. et al. WDR5 is essential for assembly of the VISA-associated signaling complex and virus-triggered IRF3 and NF-kappaB activation. Proc. Natl Acad. Sci. USA 107, 815–820 (2010).

    Article  CAS  Google Scholar 

  15. Hu, M. M. & Shu, H. B. Cytoplasmic mechanisms of recognition and defense of microbial nucleic acids. Annu Rev. Cell Dev. Biol. 34, 357–379 (2018).

    Article  CAS  Google Scholar 

  16. Hu, M. M. & Shu, H. B. Multifaceted roles of TRIM38 in innate immune and inflammatory responses. Cell Mol. Immunol. 14, 331–338 (2017).

    Article  CAS  Google Scholar 

  17. Liu, B. et al. The ubiquitin E3 ligase TRIM31 promotes aggregation and activation of the signaling adaptor MAVS through Lys63-linked polyubiquitination. Nat. Immunol. 18, 214–224 (2017).

    Article  CAS  Google Scholar 

  18. Wei, J. et al. SNX8 mediates IFNgamma-triggered noncanonical signaling pathway and host defense against Listeria monocytogenes. Proc. Natl Acad. Sci. USA 114, 13000–13005 (2017).

    Article  CAS  Google Scholar 

  19. Wei, J. et al. SNX8 modulates innate immune response to DNA virus by mediating trafficking and activation of MITA. PLoS Pathog. 14, e1007336 (2018).

    Article  Google Scholar 

  20. Johannes, L. & Wunder, C. The SNXy flavours of endosomal sorting. Nat. Cell Biol. 13, 884–886 (2011).

    Article  CAS  Google Scholar 

  21. Luo, W. W. & Shu, H. B. Delicate regulation of the cGAS-MITA-mediated innate immune response. Cell Mol. Immunol. 15, 666–675 (2018).

    Article  CAS  Google Scholar 

  22. Hu, M. M., Liao, C. Y., Yang, Q., Xie, X. Q. & Shu, H. B. Innate immunity to RNA virus is regulated by temporal and reversible sumoylation of RIG-I and MDA5. J. Exp. Med. 214, 973–989 (2017).

    Article  CAS  Google Scholar 

  23. Zhou, Q. et al. The ER-associated protein ZDHHC1 is a positive regulator of DNA virus-triggered, MITA/STING-dependent innate immune signaling. Cell Host Microbe 16, 450–461 (2014).

    Article  CAS  Google Scholar 

  24. Zhang, J., Hu, M. M., Shu, H. B. & Li, S. Death-associated protein kinase 1 is an IRF3/7-interacting protein that is involved in the cellular antiviral immune response. Cell Mol. Immunol. 11, 245–252 (2014).

    Article  CAS  Google Scholar 

  25. Liu, Y. et al. ZDHHC11 modulates innate immune response to DNA virus by mediating MITA-IRF3 association. Cell Mol. Immunol. 15, 907–916 (2018).

    Article  CAS  Google Scholar 

  26. Jiang, L. Q. et al. IFITM3 inhibits virus-triggered induction of type I interferon by mediating autophagosome-dependent degradation of IRF3. Cell Mol. Immunol. 15, 858–867 (2018).

    Article  CAS  Google Scholar 

  27. Hu, M. M. et al. Sumoylation promotes the stability of the DNA sensor cGAS and the adaptor STING to regulate the kinetics of response to DNA virus. Immunity 45, 555–569 (2016).

    Article  CAS  Google Scholar 

  28. Yang, Q. et al. TRIM32-TAX1BP1-dependent selective autophagic degradation of TRIF negatively regulates TLR3/4-mediated innate immune responses. PLoS Pathog. 13, e1006600 (2017).

    Article  Google Scholar 

  29. Zhong, B. et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29, 538–550 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the State Key R&D Program of China (2017YFA0505800, 2016YFA0502102) and the National Natural Science Foundation of China (31830024, 31800728, 31630045, 31521091, 31671465, and 31771555).

Author information

Author notes

  1. These authors contributed equally: Wei Guo, Jin Wei

Authors and Affiliations

  1. Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Medical Research Institute, Wuhan University, Wuhan, China

    Wei Guo, Jin Wei, Xuan Zhong, Ru Zang, Huan Lian, Ming-Ming Hu, Shu Li, Hong-Bing Shu & Qing Yang

Authors
  1. Wei Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xuan Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ru Zang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huan Lian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ming-Ming Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hong-Bing Shu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.B.S., Q.Y., J.W. and W.G. conceived and designed the study; W.G., J.W., X.Z., R.Z. and H.L., performed the experiments; and H.B.S., Q.Y., M.M.H., and S.L. analyzed the data. Q.Y., W.G., J.W. and H.B.S. wrote the manuscript.

Corresponding authors

Correspondence to Hong-Bing Shu or Qing Yang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, W., Wei, J., Zhong, X. et al. SNX8 modulates the innate immune response to RNA viruses by regulating the aggregation of VISA. Cell Mol Immunol 17, 1126–1135 (2020). https://doi.org/10.1038/s41423-019-0285-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-019-0285-2

Keywords

This article is cited by

Search

Advanced search

Quick links