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:

Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection

Nature Immunology volume 10, pages 480–487 (2009)Cite this article

Abstract

Viral proteins are usually processed by the 'classical' major histocompatibility complex (MHC) class I presentation pathway. Here we showed that although macrophages infected with herpes simplex virus type 1 (HSV-1) initially stimulated CD8+ T cells by this pathway, a second pathway involving a vacuolar compartment was triggered later during infection. Morphological and functional analyses indicated that distinct forms of autophagy facilitated the presentation of HSV-1 antigens on MHC class I molecules. One form of autophagy involved a previously unknown type of autophagosome that originated from the nuclear envelope. Whereas interferon-γ stimulated classical MHC class I presentation, fever-like hyperthermia and the pyrogenic cytokine interleukin 1β activated autophagy and the vacuolar processing of viral peptides. Viral peptides in autophagosomes were further processed by the proteasome, which suggests a complex interaction between the vacuolar and MHC class I presentation pathways.

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

Figure 1: A vacuolar pathway participates in the processing of endogenous viral proteins for presentation on MHC class I molecules.
Figure 2: Autophagy induced during HSV-1 infection contributes to the processing and presentation of endogenous viral antigens on MHC class I molecules.
Figure 3: Both gB and LC3 accumulate in perinuclear regions during HSV-1 infection.
Figure 4: HSV-1 induces the formation of autophagosome-like structures from the nuclear envelopes of infected macrophages.
Figure 5: The four-layered membrane structures that emerge from the nuclear envelope have autophagosome-like features.
Figure 6: Involvement of lytic vacuolar compartments in the processing and presentation of endogenous antigens on MHC class I molecules after treatment with proinflammatory cytokines.

Similar content being viewed by others

References

  1. Bevan, M.J. Cross-priming for a secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not cross-react in the cytotoxic assay. J. Exp. Med. 143, 1283–1288 (1976).

    Article  CAS  PubMed  Google Scholar 

  2. Deretic, V. Autophagy in innate and adaptive immunity. Trends Immunol. 26, 523–528 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Levine, B. & Deretic, V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat. Rev. Immunol. 7, 767–777 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schmid, D. & Munz, C. Innate and adaptive immunity through autophagy. Immunity 27, 11–21 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Andrade, R.M., Wessendarp, M., Gubbels, M.J., Striepen, B. & Subauste, C.S. CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J. Clin. Invest. 116, 2366–2377 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gutierrez, M.G. et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753–766 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Ling, Y.M. et al. Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages. J. Exp. Med. 203, 2063–2071 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nakagawa, I. et al. Autophagy defends cells against invading group A Streptococcus. Science 306, 1037–1040 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Ogawa, M. et al. Escape of intracellular Shigella from autophagy. Science 307, 727–731 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Liu, Y. et al. Autophagy regulates programmed cell death during the plant innate immune response. Cell 121, 567–577 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Orvedahl, A. et al. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1, 23–35 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Paludan, C. et al. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307, 593–596 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Dengjel, J. et al. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc. Natl. Acad. Sci. USA 102, 7922–7927 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bernales, S., Schuck, S. & Walter, P. ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy 3, 285–287 (2007).

    Article  PubMed  Google Scholar 

  15. Ackerman, A.L., Kyritsis, C., Tampe, R. & Cresswell, P. Early phagosomes in dendritic cells form a cellular compartment sufficient for cross presentation of exogenous antigens. Proc. Natl. Acad. Sci. USA 100, 12889–12894 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Houde, M. et al. Phagosomes are competent organelles for antigen cross-presentation. Nature 425, 402–406 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Guermonprez, P. et al. ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells. Nature 425, 397–402 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Mueller, S.N. et al. The early expression of glycoprotein B from herpes simplex virus can be detected by antigen-specific CD8+ T cells. J. Virol. 77, 2445–2451 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mueller, S.N., Jones, C.M., Smith, C.M., Heath, W.R. & Carbone, F.R. Rapid cytotoxic T lymphocyte activation occurs in the draining lymph nodes after cutaneous herpes simplex virus infection as a result of early antigen presentation and not the presence of virus. J. Exp. Med. 195, 651–656 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Noda, T. & Ohsumi, Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J. Biol. Chem. 273, 3963–3966 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Komata, T. et al. Mild heat shock induces autophagic growth arrest, but not apoptosis in U251-MG and U87-MG human malignant glioma cells. J. Neurooncol. 68, 101–111 (2004).

    Article  PubMed  Google Scholar 

  23. Talloczy, Z. et al. Regulation of starvation- and virus-induced autophagy by the eIF2α kinase signaling pathway. Proc. Natl. Acad. Sci. USA 99, 190–195 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. He, B., Gross, M. & Roizman, B. The γ134.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1α to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase. Proc. Natl. Acad. Sci. USA 94, 843–848 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Alexander, D.E., Ward, S.L., Mizushima, N., Levine, B. & Leib, D.A. Analysis of the role of autophagy in replication of herpes simplex virus in cell culture. J. Virol. 81, 12128–12134 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Talloczy, Z., Virgin, H.W. IV. & Levine, B. PKR-dependent autophagic degradation of herpes simplex virus type 1. Autophagy 2, 24–29 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Levine, B. Eating oneself and uninvited guests: autophagy-related pathways in cellular defense. Cell 120, 159–162 (2005).

    CAS  PubMed  Google Scholar 

  28. Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–5728 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Heldwein, E.E. et al. Crystal structure of glycoprotein B from herpes simplex virus 1. Science 313, 217–220 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Stannard, L.M., Himmelhoch, S. & Wynchank, S. Intra-nuclear localization of two envelope proteins, gB and gD, of herpes simplex virus. Arch. Virol. 141, 505–524 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Farnsworth, A. et al. Herpes simplex virus glycoproteins gB and gH function in fusion between the virion envelope and the outer nuclear membrane. Proc. Natl. Acad. Sci. USA 104, 10187–10192 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Khalkhali-Ellis, Z. et al. IFN-γ regulation of vacuolar pH, cathepsin D processingand autophagy in mammary epithelial cells. J. Cell. Biochem. 105, 208–218 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Griffin, T.A. et al. Immunoproteasome assembly: cooperative incorporation of interferon γ (IFN-γ)-inducible subunits. J. Exp. Med. 187, 97–104 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Epperson, D.E. et al. Cytokines increase transporter in antigen processing-1 expression more rapidly than HLA class I expression in endothelial cells. J. Immunol. 149, 3297–3301 (1992).

    CAS  PubMed  Google Scholar 

  35. Conti, B., Tabarean, I., Andrei, C. & Bartfai, T. Cytokines and fever. Front. Biosci. 9, 1433–1449 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Jarvis, M.A. et al. Human cytomegalovirus attenuates interleukin-1β and tumor necrosis factor α proinflammatory signaling by inhibition of NF-κB activation. J. Virol. 80, 5588–5598 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kovacsovics-Bankowski, M. & Rock, K.L. A phagosome-to-cytosol pathway for exogenous antigens presented on MHC class I molecules. Science 267, 243–246 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Ackerman, A.L., Giodini, A. & Cresswell, P. A role for the endoplasmic reticulum protein retrotranslocation machinery during crosspresentation by dendritic cells. Immunity 25, 607–617 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Jackson, W.T. et al. Subversion of cellular autophagosomal machinery by RNA viruses. PLoS Biol. 3, e156 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Desai, P. & Person, S. Incorporation of the green fluorescent protein into the herpes simplex virus type 1 capsid. J. Virol. 72, 7563–7568 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Bolovan, C.A., Sawtell, N.M. & Thompson, R.L. ICP34.5 mutants of herpes simplex virus type 1 strain 17syn+ are attenuated for neurovirulence in mice and for replication in confluent primary mouse embryo cell cultures. J. Virol. 68, 48–55 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Griffiths, G., Quinn, P. & Warren, G. Dissection of the Golgi complex. I. Monensin inhibits the transport of viral membrane proteins from medial to trans Golgi cisternae in baby hamster kidney cells infected with Semliki Forest virus. J. Cell Biol. 96, 835–850 (1983).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank J. Thibodeau and C. Perreault for critical reading of the manuscript; K. Rock (University of Massachusetts Medical School) for BMA cells; W. Heath (University of Melbourne) for the HSV-2.3.2E2 hybridoma; G. Arthur (University of Manitoba) for the wild-type and Atg5−/− mouse embryonic fibroblasts produced by N. Mizushima (Medical and Dental University, Tokyo); P. Desai (Johns Hopkins University) for the HSV-1 K26-GFP mutant; and M. Bendayan for assistance with electron microscopy. Supported by the Canadian Institutes for Health Research (R.L. and M.D.), the Natural Science and Engineering Research Council of Canada (L.E.), Fonds de la Recherche en Santé du Québec (L.E.), the US National Institutes of Health (EY09083) and Research to Prevent Blindness (D.L.)

Author information

Authors and Affiliations

  1. Département de Pathologie et Biologie Cellulaire, Université de Montréal, Succursale Centre-Ville, Montreal, Quebec, Canada

    Luc English, Magali Chemali, Johanne Duron, Christiane Rondeau, Annie Laplante, Diane Gingras, Roger Lippé & Michel Desjardins

  2. Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA

    Diane Alexander & David Leib

  3. Department of Microbiology and Immunology, Pennsylvania State University, Milton S. Hershey College of Medicine, Hershey, Pennsylvania, USA

    Christopher Norbury

  4. Département de microbiologie et immunologie, Université de Montréal, Succursale Centre-Ville, Montreal, Quebec, Canada

    Michel Desjardins

  5. Caprion Pharmaceuticals, Montréal, Québec, Canada

    Michel Desjardins

Authors
  1. Luc English
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Magali Chemali
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johanne Duron
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christiane Rondeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Annie Laplante
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Diane Gingras
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Diane Alexander
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David Leib
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christopher Norbury
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Roger Lippé
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michel Desjardins
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.E. planned and did most of the experiments and actively participated in writing the manuscript; M.C. did the experiments with mouse embryonic fibroblasts; J.D. maintained viral stocks; C.R. did the technical work for Epon electron microscopy; A.L. provided technical assistance for immunoblot analysis and immunofluorescence; D.G. did the immunogold labeling and morphological quantification; D.A. and D.L. produced the ICP34.5 HSV-1 mutant; C.N. participated in the planning and development of the antigen-presentation assay and provided help in writing the manuscript; R.L. provided HSV-1 virus stocks and expertise with the infection system and helped write the manuscript; and M.D. planned and directed the work and wrote the manuscript.

Corresponding author

Correspondence to Michel Desjardins.

Ethics declarations

Competing interests

M.D. is a consultant for Caprion Pharmaceuticals for their program on brucella.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 (PDF 7265 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

English, L., Chemali, M., Duron, J. et al. Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Nat Immunol 10, 480–487 (2009). https://doi.org/10.1038/ni.1720

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1720

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