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.

  • Progress
  • Published:

Beyond Tsg101: the role of Alix in 'ESCRTing' HIV-1

Abstract

The limited coding capacity of retroviral genomes forces these viruses to rely heavily on the host-cell machinery for their replication. This phenomenon is particularly well illustrated by the interaction between retroviruses and components of the endosomal budding machinery that occurs during virus release. Here, we focus on the use of host-cell factors during HIV-1 budding and highlight recent progress in our understanding of the role of one such factor, Alix, in both viral and cellular membrane budding and fission events.

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

Access options

Buy this article

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

Figure 1: Organization of retroviral Gag proteins.
Figure 2: The ESCRT machinery, and HIV-1 budding from the plasma membrane.
Figure 3: Domain organization and structure of Alix.

Similar content being viewed by others

References

  1. Swanstrom, R. & Wills, J. W. in Synthesis, Assembly, and Processing of Viral Proteins 263–334 (Cold Spring Harbor Laboratory Press, New York, 1997).

    Google Scholar 

  2. Freed, E. O. HIV-1 gag proteins: diverse functions in the virus life cycle. Virology 251, 1–15 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Gottlinger, H. G., Dorfman, T., Sodroski, J. G. & Haseltine, W. A. Effect of mutations affecting the p6 gag protein on human immunodeficiency virus particle release. Proc. Natl Acad. Sci. USA 88, 3195–3199 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Huang, M., Orenstein, J. M., Martin, M. A. & Freed, E. O. p6Gag is required for particle production from full-length human immunodeficiency virus type 1 molecular clones expressing protease. J. Virol. 69, 6810–6818 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Puffer, B. A., Parent, L. J., Wills, J. W. & Montelaro, R. C. Equine infectious anemia virus utilizes a YXXL motif within the late assembly domain of the Gag p9 protein. J. Virol. 71, 6541–6546 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Wills, J. W. et al. An assembly domain of the Rous sarcoma virus Gag protein required late in budding. J. Virol. 68, 6605–6618 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Bieniasz, P. D. Late budding domains and host proteins in enveloped virus release. Virology 344, 55–63 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Demirov, D. G. & Freed, E. O. Retrovirus budding. Virus Res. 106, 87–102 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Morita, E. & Sundquist, W. I. Retrovirus budding. Annu. Rev. Cell Dev. Biol. 20, 395–425 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Katzmann, D. J., Odorizzi, G. & Emr, S. D. Receptor downregulation and multivesicular-body sorting. Nature Rev. Mol. Cell Biol. 3, 893–905 (2002).

    Article  CAS  Google Scholar 

  11. Garrus, J. E. et al. Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell 107, 55–65 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. VerPlank, L. et al. Tsg101, a homologue of ubiquitin-conjugating (E2) enzymes, binds the L domain in HIV type 1 Pr55Gag. Proc. Natl Acad. Sci. USA 98, 7724–7729 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Demirov, D. G., Ono, A., Orenstein, J. M. & Freed, E. O. Overexpression of the N-terminal domain of TSG101 inhibits HIV-1 budding by blocking late domain function. Proc. Natl Acad. Sci. USA 99, 955–960 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Martin-Serrano, J., Zang, T. & Bieniasz, P. D. HIV-1 and Ebola virus encode small peptide motifs that recruit Tsg101 to sites of particle assembly to facilitate egress. Nature Med. 7, 1313–1319 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Odorizzi, G. The multiple personalities of Alix. J. Cell Sci. 119, 3025–3032 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Fisher, R. D. et al. Structural and biochemical studies of ALIX/AIP1 and its role in retrovirus budding. Cell 128, 841–852 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Hurley, J. H. & Emr, S. D. The ESCRT complexes: structure and mechanism of a membrane-trafficking network. Annu. Rev. Biophys. Biomol. Struct. 35, 277–298 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kim, J. et al. Structural basis for endosomal targeting by the Bro1 domain. Dev. Cell 8, 937–947 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Schmidt, M. H., Dikic, I. & Bogler, O. Src phosphorylation of Alix/AIP1 modulates its interaction with binding partners and antagonizes its activities. J. Biol. Chem. 280, 3414–3425 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Lee, S., Joshi, A., Nagashima, K., Freed, E. O. & Hurley, J. H. Structural basis for viral late-domain binding to Alix. Nature Struct. Mol. Biol. 14, 194–199 (2007).

    Article  CAS  Google Scholar 

  21. Missotten, M., Nichols, A., Rieger, K. & Sadoul, R. Alix, a novel mouse protein undergoing calcium-dependent interaction with the apoptosis-linked-gene 2 (ALG-2) protein. Cell Death Differ. 6, 124–129 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Vito, P., Pellegrini, L., Guiet, C. & D'Adamio, L. Cloning of AIP1, a novel protein that associates with the apoptosis-linked gene ALG-2 in a Ca2+-dependent reaction. J. Biol. Chem. 274, 1533–1540 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Trioulier, Y. et al. Alix, a protein regulating endosomal trafficking, is involved in neuronal death. J. Biol. Chem. 279, 2046–2052 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Martin-Serrano, J., Yarovoy, A., Perez-Caballero, D. & Bieniasz, P. D. Divergent retroviral late-budding domains recruit vacuolar protein sorting factors by using alternative adaptor proteins. Proc. Natl Acad. Sci. USA 100, 12414–12419 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Strack, B., Calistri, A., Craig, S., Popova, E. & Gottlinger, H. G. AIP1/ALIX is a binding partner for HIV-1 p6 and EIAV p9 functioning in virus budding. Cell 114, 689–699 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. von Schwedler, U. K. et al. The protein network of HIV budding. Cell 114, 701–713 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Chen, C., Vincent, O., Jin, J., Weisz, O. A. & Montelaro, R. C. Functions of early (AP-2) and late (AIP1/ALIX) endocytic proteins in equine infectious anemia virus budding. J. Biol. Chem. 280, 40474–40480 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Demirov, D. G., Orenstein, J. M. & Freed, E. O. The late domain of human immunodeficiency virus type 1 p6 promotes virus release in a cell type-dependent manner. J. Virol. 76, 105–117 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Munshi, U. M., Kim, J., Nagashima, K., Hurley, J. H. & Freed, E. O. An Alix fragment potently inhibits HIV-1 budding: characterization of binding to retroviral YPXL late domains. J. Biol. Chem. 282, 3847–3855 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Usami, Y., Popov, S. & Gottlinger, H. G. Potent rescue of human immunodeficiency virus type 1 late domain mutants by ALIX/AIP1 depends on its CHMP4 binding site. J. Virol. 81, 6614–6622 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Carlton, J. G. & Martin-Serrano, J. Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery. Science 316, 1908–1912 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Fabbro, M. et al. Cdk1/Erk2- and Plk1-dependent phosphorylation of a centrosome protein, Cep55, is required for its recruitment to midbody and cytokinesis. Dev. Cell 9, 477–488 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Ichioka, F. et al. HD-PTP and Alix share some membrane-traffic related proteins that interact with their Bro1 domains or proline-rich regions. Arch. Biochem. Biophys. 457, 142–149 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Morita, E. et al. Identification of human MVB12 proteins as ESCRT-I subunits that functions in HIV budding. Cell Host Microbe 2, 41–53 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Horii, M. et al. CHMP7, a novel ESCRT-III-related protein, associates with CHMP4b and functions in the endosomal sorting pathway. Biochem. J. 400, 23–32 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jouvenet, N. et al. Plasma membrane is the site of productive HIV-1 particle assembly. PLoS Biol. 4, e435 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Booth, A. M. et al. Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J. Cell Biol. 172, 923–935 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Deneka, M., Pelchen-Matthews, A., Byland, R., Ruiz-Mateos, E. & Marsh, M. In macrophages, HIV-1 assembles into an intracellular plasma membrane domain containing the tetraspanins CD81, CD9, and CD53. J. Cell Biol. 177, 329–341 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Welsch, S. et al. HIV-1 buds predominantly at the plasma membrane of primary human macrophages. PLoS Pathog. 3, e36 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Nydegger, S., Foti, M., Derdowski, A., Spearman, P. & Thali, M. HIV-1 egress is gated through late endosomal membranes. Traffic 4, 902–910 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Perlman, M. & Resh, M. D. Identification of an intracellular trafficking and assembly pathway for HIV-1 gag. Traffic 7, 731–745 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank W. S. Hu, V. Pathak and members of the Freed laboratory for the critical review of the manuscript. Work in the authors' laboratories is supported by intramural grant support from the Center for Cancer Research, the National Cancer Institute, the National Institute of Diabetes and Digestive and Kidney Diseases and the Intramural AIDS Targeted Antiviral Program.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eric O. Freed.

Related links

Related links

DATABASES

Entrez Genome

EIAV

HIV-1

RSV

SIV

Entrez Protein

Alix

EIAV Gag

HIV-1 Gag

Pr55Gag

FURTHER INFORMATION

Eric O. Freed's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fujii, K., Hurley, J. & Freed, E. Beyond Tsg101: the role of Alix in 'ESCRTing' HIV-1. Nat Rev Microbiol 5, 912–916 (2007). https://doi.org/10.1038/nrmicro1790

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro1790

This article is cited by

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