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.

  • Journal Club
  • Published:

Path to autophagy therapeutics with Beth Levine

Nature Reviews Molecular Cell Biology volume 21, pages 564–565 (2020)Cite this article

Subjects

Beclin 1 is a key regulator of autophagy and cell death. It was discovered in a yeast 2-hybrid screen by Beth Levine in 1998 as a novel interactor of anti-apoptotic protein, BCL-2 (Liang et al., 1998). Following on from the identification of Beclin 1, in 1999, Beth’s group made a set of truly remarkable discoveries that linked the conserved process of autophagy with human disease (Liang, Jackson et al., 1999). They found that Beclin 1 is a homologue of yeast protein Vps30, also identified as Apg6 (now known as Atg6), corresponding to its two cellular functions: in vacuolar protein sorting and autophagy, respectively. Interestingly, in yeast Atg6/Vps30 mutants, expression of human Beclin 1 could restore defects of autophagy but not defects of vacuolar protein delivery. We now understand that Beclin 1 is part of two complexes: one required for autophagy and one required for endocytic function. In the same study, Beth also showed that Beclin 1 was mono-allelically deleted in breast and ovarian cancers, indicating the role of Beclin 1 as a tumour suppressor. This was a fundamental advance that changed the history of autophagy research. Further studies confirmed in mice that Beclin 1 has anti-tumorigenic function, which coincides with autophagy induction. It is now apparent that Beclin 1 is post-translationally modified by multiple signalling pathways involved in cell proliferation and survival leading to cancer and acts as a rheostat both inhibiting and inducing autophagy. And so, the link between autophagy and tumorigenesis, albeit complex, was forged by Beth’s discovery of Beclin 1.

Autophagy is also involved in the regulation of viral replication and infection. Going back to 1998, the 2-hybrid screen for BCL-2-interacting proteins was performed to understand how BCL-2 protects cells against Sindbis virus infection. Fast forward to 2013, and Beth’s group is asking how virulence factors work to modulate autophagy for the benefit of the virus (Shoji-Kawata et al., 2013). Using a complimentary set of approaches and once again homology with Atg6, Beth’s group designed an 18 amino acid peptide derived from Beclin 1 and attached it to a protein transduction domain of HIV protein Tat (called Tat–Beclin 1), which was cell-permeable and able to induce autophagy in vitro and in vivo. This peptide was a first attempt to therapeutically induce autophagy aiming to modulate or prevent diseases caused by insufficient or perturbed autophagic responses, such as neurodegenerative disorders, infection or cancer. Following on this seminal work, various approaches to modulate autophagy are now in clinical trials (for a Review, see Dikic & Elazar, 2018).

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

References

Original articles

  • Liang, X. H. et al. Protection against Fatal Sindbis Virus Encephalitis by Beclin. J. Virol. 72, 8586–8596 (1998)

    Article  CAS  Google Scholar 

  • Liang, X. H. et al. Induction of autophagy and inhibition of tumorgenesis by beclin 1. Nature 402, 672–676 (1999)

    Article  CAS  Google Scholar 

  • Shoji-Kawata, S. R. et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201–206 (2013)

    Article  CAS  Google Scholar 

  • Virgin, H. W., Cuervo, A. M. & Xavier, R. J. Beth Cindy Levine (1960–2020). Science 369, 378 (2020)

    CAS  PubMed  Google Scholar 

Related article

  • Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018)

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Francis Crick Institute, London, UK

    Sharon A. Tooze

Authors
  1. Sharon A. Tooze
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sharon A. Tooze.

Ethics declarations

Competing interests

The author declares no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tooze, S.A. Path to autophagy therapeutics with Beth Levine. Nat Rev Mol Cell Biol 21, 564–565 (2020). https://doi.org/10.1038/s41580-020-00282-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41580-020-00282-1

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