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:

Forced degradation of Fas inhibits apoptosis in adenovirus-infected cells

Abstract

DNA viruses have evolved elaborate mechanisms to overcome host antiviral defences. In adenovirus-infected cells, programmed cell death (apoptosis) induced by the cytokine tumour necrosis factor (TNF) is inhibited by several adenovirus-encoded proteins1,2,3. Occupation of the cell-surface receptor Fas, a member of the TNF-receptor superfamily that is expressed on most cell types, triggers apoptosis of that cell4,5,6. Here we show that the adenovirus RID (for receptor internalization and degradation) protein complex, which is an inhibitor of TNF-induced apoptosis2, mediates internalization of cell-surface Fas and its destruction inside lysosomes within the cell. Fas has not previously been shown to be internalized and then degraded. RID also mediates internalization of the receptor for epidermal growth factor7,8, but it does not affect the transferrin receptor or class I antigens of the major histocompatibility complex. Removal of Fas from the surface of adenovirus-infected cells expressing RID may allow infected cells to resist Fas-mediated cell death and thus promote their survival.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: RID is required for inhibition of apoptosis induced by Fas agonist, internalization of cell-surface Fas, and degradation of Fas in MCF7-Fas cells infected with adenovirus mutants.
Figure 2: Fas colocalizes with LAMP-1 in lysosomes in rec700-infected cells.
Figure 3: Bafilomycin A1 (Baf) inhibits RID-mediated degradation of Fas.
Figure 4: The presence of RID is sufficient to internalize cell-surface Fas into vesicles in COS cells transiently cotransfected with RID-α, RID-β, and Fas.
Figure 5: RID is needed to inhibit killing of adenovirus-infected P815 cells by CTLs from perforin−/− mice.

Similar content being viewed by others

References

  1. Gooding, L. R., Elmore, L. W., Tollefson, A. E., Brady, H. A. & Wold, W. S. M. A. 14,700 MW protein from the E3 region of adenovirus inhibits cytolysis by tumor necrosis factor. Cell 53, 341–346 (1988).

    Article  CAS  Google Scholar 

  2. Gooding, L. R. et al. The 10,400- and 14,500-dalton proteins encoded by region E3 of adenovirus function together to protect many but not all mouse cell lines against lysis by tumor necrosis factor. J.Virol. 65, 4114–4123 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Gooding, L. R. et al. The E1B 19,000-molecular-weight protein of group C adenoviruses prevents tumor necrosis factor cytolysis of human cells but not of mouse cells. J. Virol. 65, 3083–3094 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Nagata, S. Apoptosis by death factor. Cell 88, 355–365 (1997).

    Article  CAS  Google Scholar 

  5. Itoh, N. et al. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66, 233–243 (1991).

    Article  CAS  Google Scholar 

  6. Oehm, A. et al. Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily. J. Biol. Chem. 267, 10709–10715 (1992).

    CAS  PubMed  Google Scholar 

  7. Carlin, C. R., Tollefson, A. E., Brady, H. A., Hoffman, B. L. & Wold, W. S. M. Epidermal growth factor receptor is down-regulated by a 10,400 MW protein encoded by the E3 region of adenovirus. Cell 57, 135–144 (1989).

    Article  CAS  Google Scholar 

  8. Tollefson, A. E., Stewart, A. R., Yei, S. P., Saha, S. K. & Wold, W. S. M. The 10,400- and 14,500-dalton proteins encoded by region E3 of adenovirus form a complex and function together to down-regulate the epidermal growth factor receptor. J. Virol. 65, 3095–3105 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Tollefson, A. E., Krajcsi, P., Yei, S. P., Carlin, C. R. & Wold, W. S. M. A10,400-molecular-weight membrane protein is coded by region E3 of adenovirus. J. Virol. 64, 794–801 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Tollefson, A. E., Krajcsi, P., Pursley, M. H., Gooding, L. R. & Wold, W. S. M. A14,500 MW protein is coded by region E3 of group C human adenoviruses. Virology 175, 19–29 (1990).

    Article  CAS  Google Scholar 

  11. Hashimoto, S., Ishii, A. & Yonehara, S. The E1b oncogene of adenovirus confers cellular resistance to cytotoxicity of tumor necrosis factor and monoclonal anti-Fas antibody. Int. Immunol. 3, 343–351 (1991).

    Article  CAS  Google Scholar 

  12. Boyd, J. M. et al. Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. Cell 79, 341–351 (1994).

    Article  CAS  Google Scholar 

  13. White, E. Life, death, and the pursuit of apoptosis. Genes Dev. 10, 1–15 (1996).

    Article  CAS  Google Scholar 

  14. Hoffman, P., Yaffe, M. B., Hoffman, B. L., Yei, S., Wold, W. S. M. & Carlin, C. Characterization of the adenovirus E3 protein that down-regulates the epidermal growth factor receptor. Evidence for intermolecular disulfide bonding and plasma membrane localization. J. Biol. Chem. 267, 13480–13487 (1992).

    CAS  PubMed  Google Scholar 

  15. Stewart, A. R., Tollefson, A. E., Krajcsi, P., Yei, S. P. & Wold, W. S. M. The adenovirus E3 10.4K and 14.5K proteins, which function to prevent cytolysis by tumor necrosis factor and to down-regulate the epidermal growth factor receptor, are localized in the plasma membrane. J. Virol. 69, 172–181 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Carlsson, S. R., Roth, J., Piller, F. & Fukuda, M. Isolation and characterization of human lysosomal membrane glycoproteins, h-lamp-1 and h-lamp-2. Major sialoglycoproteins carrying polylactosaminoglycan. J. Biol. Chem. 15, 18911–18919 (1988).

    Google Scholar 

  17. Yoshimori, T., Yamamoto, A., Moriyama, Y., Futai, M. & Tashiro, Y. Bafilomycin A1, a specific inhibitor of vacuolar-type H+-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J. Biol. Chem. 266, 17707–17712 (1991).

    CAS  PubMed  Google Scholar 

  18. van Weert, A. W. M., Dunn, K. W., Geuze, H. J., Maxfield, F. R. & Stoorvogel, W. Transport from late endosomes to lysosomes, but not sorting of integral membrane proteins in endosomes, depends on the vacuolar proton pump. J. Cell. Biol. 130, 821–834 (1995).

    Article  CAS  Google Scholar 

  19. Mazzarella, R. A., Srinivasan, M., Haugejorden, S. & Green, M. ERp72, an abundant, luminal ER protein, contains three copies of the active site sequences of protein disulfide isomerase. J. Biol. Chem. 265, 1094–1101 (1990).

    CAS  PubMed  Google Scholar 

  20. Clark, W. R. et al. Molecular pathways of CTL-mediated cytotoxicity. Immunol. Rev. 146, 33–44 (1995).

    Article  CAS  Google Scholar 

  21. Azuma, M., Cayabyab, M., Buck, D., Phillips, J. H. & Lanier, L. L. CD28 interaction with B7 costimulates primary allogeneic proliferative responses and cytotoxicity mediated by small, resting T lymphocytes. J. Exp. Med. 175, 353–360 (1992).

    Article  CAS  Google Scholar 

  22. Kagi, D. et al. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 265, 528–530 (1994).

    Article  ADS  CAS  Google Scholar 

  23. Brunner, T. et al. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 373, 441–444 (1995).

    Article  ADS  CAS  Google Scholar 

  24. Dhein, J., Walczak, H., Baumler, C., Debatin, K.-M. & Krammer, P. H. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature 373, 438–441 (1995).

    Article  ADS  CAS  Google Scholar 

  25. Ju, S.-T. et al. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373, 444–448 (1995).

    Article  ADS  CAS  Google Scholar 

  26. Jäättela, M., Benedict, M., Tewari, M., Shayman, J. A. & Dixit, V. M. Bcl-x and Bcl-2 inhibit TNF and Fas-induced apoptosis and activation of phospholipase A2 in breast carcinoma cells. Oncogene 10, 2297–2305 (1995).

    PubMed  Google Scholar 

  27. Subramanian, T., Kuppuswamy, M., Mak, S. & Chinnadurai, G. Adenovirus cyt+ locus, which controls cell transformation and tumorigenicity, is an allele of lp+ locus, which codes for a 19-kilodalton tumor antigen. J. Virol. 52, 336–343 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Babiss, L. E., Fisher, P. B. & Ginsberg, H. S. Effect on transformation of mutations in the early region 1b-encoded 21- and 55-kilodalton proteins of adenovirus 5. J. Virol. 52, 389–395 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ranheim, T. S. et al. Characterization of mutants within the gene for the adenovirus E3 14.7-kilodalton protein which prevents cytolysis by tumor necrosis factor. J. Virol. 67, 2159–2167 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Tripp, R. A., Hou, S., McMickle, A., Houston, J. & Doherty, P. C. Recruitment and proliferation of CD8+ T cells in respiratory virus infections. J. Immunol. 154, 6013–6021 (1995).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank J. Freeman for help with the confocal microscopy, V. Dixit for the MCF7 and MCF7-Fas cell lines and for pcDNA-3-Fas, M. Green for the pMT2 vector, the ERp72 antiserum, and COS7 cells, M. Green for the DBP antiserum, M. Fukuda for LAMP1 antiserum, E. Harlow for the M73 mAb, C. Gugliemo for technical assistance, J. Mikes for preparation of the manuscript and figures, and C.Pollack for photography.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to William S. M. Wold.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tollefson, A., Hermiston, T., Lichtenstein, D. et al. Forced degradation of Fas inhibits apoptosis in adenovirus-infected cells. Nature 392, 726–730 (1998). https://doi.org/10.1038/33712

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/33712

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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