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.

  • Letter
  • Published:

Sphingolipid biosynthesis induces a conformational change in the murine norovirus receptor and facilitates viral infection

Nature Microbiology volume 3, pages 1109–1114 (2018)Cite this article

Subjects

Abstract

Cellular susceptibility to viral infections is in part determined by the presence of a host cellular receptor. Here we use murine norovirus as a model to uncover an unappreciated connection between an intracellular lipid biosynthetic enzyme and a receptor conformation that is permissive for viral infection. The serine palmitoyltransferase complex is required for de novo sphingolipid biosynthesis and we find that its absence impairs the ability of murine norovirus to bind and enter cells. Although the serine palmitoyltransferase complex is dispensable for the surface expression of the norovirus receptor, CD300lf, serine palmitoyltransferase activity is required for CD300lf to adopt a conformation permissive for viral binding. Addition of extracellular ceramide to serine palmitoyltransferase-deficient cells chemically complements both the conformational changes of CD300lf and the cellular susceptibility to murine norovirus infection. Taken together, these data indicate that intracellular sphingolipid biosynthesis regulates the conformation of the murine norovirus receptor and therefore the tropism of murine norovirus. This indicates that intracellular biosynthetic pathways can regulate viral tropism even when the receptor for a virus is expressed on the target cell surface.

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: De novo ceramide biosynthesis is required for efficient MNoV infection, binding and entry.
Fig. 2: Sptlc2 is not required for CD300lf surface localization.
Fig. 3: Ceramide biosynthesis is required for a functional CD300lf conformation.
Fig. 4: Chemical complementation restores MNoV infection and a CD300lf conformation in Sptlc2-deficient cells.

Similar content being viewed by others

References

  1. Glass, R. I., Parashar, U. D. & Estes, M. K. Norovirus gastroenteritis. N. Engl. J. Med. 361, 1776–1785 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Bok, K. & Green, K. Y. Norovirus gastroenteritis in immunocompromised patients. N. Engl. J. Med. 367, 2126–2132 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Karst, S. M., Wobus, C. E., Goodfellow, I. G., Green, K. Y. & Virgin, H. W. Advances in norovirus biology. Cell Host Microbe 15, 668–680 (2014).

  4. Guix, S. et al. Norwalk virus RNA is infectious in mammalian cells. J. Virol. 81, 12238–12248 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Orchard, R. C. et al. Discovery of a proteinaceous cellular receptor for a norovirus. Science 353, 933–936 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Haga, K. et al. Functional receptor molecules CD300lf and CD300ld within the CD300 family enable murine noroviruses to infect cells. Proc. Natl Acad. Sci. USA 113, E6248–E6255 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Lindesmith, L. et al. Human susceptibility and resistance to Norwalk virus infection. Nat. Med. 9, 548–553 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Kambhampati, A., Payne, D. C., Costantini, V. & Lopman, B. A. Host genetic susceptibility to enteric viruses: a systematic review and metaanalysis. Clin. Infect. Dis. 62, 11–18 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Wobus, C. E. et al. Replication of Norovirus in cell culture reveals a tropism for dendritic cells and macrophages. PLoS Biol. 2, e432 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Karst, S. M., Wobus, C. E., Lay, M., Davidson, J. & Virgin, H. W. STAT1-dependent innate immunity to a Norwalk-like virus. Science 299, 1575–1578 (2003).

    Article  CAS  Google Scholar 

  11. Hanada, K. Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism. Biochim. Biophys. Acta 1632, 16–30 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Montes, L. R., Ruiz-Argüello, M. B., Goñi, F. M. & Alonso, A. Membrane restructuring via ceramide results in enhanced solute efflux. J. Biol. Chem. 277, 11788–11794 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Stancevic, B. & Kolesnick, R. Ceramide-rich platforms in transmembrane signaling. FEBS Lett. 584, 1728–1740 (2010).

  14. Fucho, R., Casals, N., Serra, D. & Herrero, L. Ceramides and mitochondrial fatty acid oxidation in obesity. FASEB J. 31, 1263–1272 (2017).

    Article  CAS  PubMed  Google Scholar 

  15. Gomez-Muñoz, A. et al. Control of inflammatory responses by ceramide, sphingosine 1-phosphate and ceramide 1-phosphate. Prog. Lipid Res. 61, 51–62 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. Galadari, S., Rahman, A., Pallichankandy, S. & Thayyullathil, F. Tumor suppressive functions of ceramide: evidence and mechanisms. Apoptosis 20, 689–711 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. Lowther, J. et al. Role of a conserved arginine residue during catalysis in serine palmitoyltransferase. FEBS Lett. 585, 1729–1734 (2011).

  18. Izawa, K. et al. The receptor LMIR3 negatively regulates mast cell activation and allergic responses by binding to extracellular ceramide. Immunity 37, 827–839 (2012).

  19. Jones, M. K. et al. Enteric bacteria promote human and mouse norovirus infection of B cells. Science 346, 755–759 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ettayebi, K.et al. Replication of human noroviruses in stem cell-derived human enteroids. Science 353, 1387–1393 (2016).

  21. Schneider-Schaulies, J. & Schneider-Schaulies, S. Sphingolipids in viral infection. Biol. Chem. 396, 585–595 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Luisoni, S. et al. Co-option of membrane wounding enables virus penetration into cells. Cell Host Microbe 18, 75–85 (2015).

  23. Otsuki, N. et al. Both Sphingomyelin and Cholesterol in the Host Cell Membrane Are Essential for Rubella Virus Entry. J Virol. 92, 17 (2018).

    Article  Google Scholar 

  24. Contreras, F. X. et al. Molecular recognition of a single sphingolipid species by a protein’s transmembrane domain. Nature 481, 525–529 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. García-Arribas, A. B., Alonso, A. & Goñi, F. M. Cholesterol interactions with ceramide and sphingomyelin. Chem. Phys. Lipids 199, 26–34 (2016).

  26. Wei, W. et al. ICAM-5/Telencephalin is a functional entry receptor for Enterovirus D68. Cell Host Microbe 20, 631–641 (2016).

  27. Farzan, M. et al. Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. Cell 96, 667–676 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Strong, D. W., Thackray, L. B., Smith, T. J. & Virgin, H. W. Protruding domain of capsid protein is necessary and sufficient to determine murine norovirus replication and pathogenesis in vivo. J. Virol. 86, 2950–2958 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hwang, S. et al. Murine norovirus: propagation, quantification, and genetic manipulation. Curr. Protoc. Microbiol. 33, 15K.2.1–15K.2.61 (2014).

    PubMed Central  Google Scholar 

  30. Baert, L. et al. Detection of murine norovirus 1 by using plaque assay, transfection assay, and real-time reverse transcription-PCR before and after heat exposure. Appl. Environ. Microbiol. 74, 543–546 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Leon Hsieh for technical assistance for MNoV binding assay. R.C.O. was supported by NIH grant K99 DK116666. C.B.W was supported by NIH grant K08 AI128043. H.W.V. was supported by NIH grants U19 AI10972505 and R01 AI127552.

Author information

Author notes

  1. Robert C. Orchard

    Present address: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    Robert C. Orchard, Craig B. Wilen & Herbert W. Virgin

Authors
  1. Robert C. Orchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Craig B. Wilen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Herbert W. Virgin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.C.O. designed, performed and analysed the experiments and wrote the manuscript. C.W.B. and H.W.V. designed and analysed the experiments. All authors read, discussed and edited the manuscript.

Corresponding authors

Correspondence to Robert C. Orchard or Herbert W. Virgin.

Ethics declarations

Competing interests

Washington University School of Medicine holds patents on several aspects of murine norovirus. These have been licensed, generating income for the University and the inventors, including H.W.V.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Orchard, R.C., Wilen, C.B. & Virgin, H.W. Sphingolipid biosynthesis induces a conformational change in the murine norovirus receptor and facilitates viral infection. Nat Microbiol 3, 1109–1114 (2018). https://doi.org/10.1038/s41564-018-0221-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41564-018-0221-8

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