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 to the Editor
  • Published:

An all-in-one targeted protein degradation platform guided by degradation condensates-bridging bi-specific nanobodies

Cell Research (2024)Cite this article

Subjects

Dear Editor,

Targeted protein degradation (TPD) has emerged as a breakthrough strategy in revolutionizing drug discovery for the currently undruggable targets. However, E3 ligase-based targeted degradation chimeras, such as proteolysis-targeting chimeras (PROTACs), are limited by the specificity of E3 ligases and the requirement for ubiquitination.1 Some innovative TPD strategies like LYTAC, AUTAC, ATTEC, AUTOTAC often rely predominantly on single degradation pathways, which restricts their versatility in degrading proteins across various cellular compartments.2,3,4,5 In this context, it is imperative to establish a universal TPD platform that can harness degradation-related liquid–liquid phase-separated droplets, which are defined as degradation condensates, to effectively target a multitude of proteins of interest (POIs). Sequestosome 1 (p62 or SQSTM1) bodies are notable representatives of such degradation condensates, which bridge the gap between the ubiquitin–proteasome system (UPS) and the autophagy-lysosome pathway (ALP) by initiating liquid–liquid phase separation (LLPS) to integrate degradation-related components.6,7 In this study, we developed a highly modular and precise platform termed the P62 Degradation Factory based on a BI-specific Nanobody (PDF-Bin), in which an engineered nanobody bridges POIs to p62 bodies for subsequent breakdown.

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: Construction of the general PDF-Bin platform.

References

  1. Pettersson, M. & Crews, C. M. Drug Discov. Today Technol. 31, 15–27 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  2. Banik, S. M. et al. Nature 584, 291–297 (2020).

    Article  ADS  CAS  PubMed Central  PubMed  Google Scholar 

  3. Takahashi, D. et al. Mol. Cell 76, 797–810.e10 (2019).

    Article  CAS  PubMed  Google Scholar 

  4. Li, Z. et al. Nature 575, 203–209 (2019).

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Ji, C. H. et al. Nat. Commun. 13, 904 (2022).

    Article  ADS  CAS  PubMed Central  PubMed  Google Scholar 

  6. Sun, D., Wu, R., Zheng, J., Li, P. & Yu, L. Cell Res. 28, 405–415 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Fu, A., Cohen-Kaplan, V., Avni, N., Livneh, I. & Ciechanover, A. Proc. Natl. Acad. Sci. USA 118, e2107321118 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Moutel, S. et al. Elife 5, e16228 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  9. Xu, W. et al. Cell Rep. 36, 109482 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Kubala, M. H., Kovtun, O., Alexandrov, K. & Collins, B. M. Protein Sci. 19, 2389–2401 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Feng, X. et al. Cell Res. 32, 659–669 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Yang, Y. et al. Nat. Commun. 10, 3759 (2019).

    Article  ADS  PubMed Central  PubMed  Google Scholar 

  13. Zhao, C. et al. Trends Pharmacol. Sci. 37, 47–61 (2016).

    Article  PubMed  Google Scholar 

  14. La Sala, G. et al. Nat. Commun. 11, 4115 (2020).

    Article  ADS  PubMed Central  PubMed  Google Scholar 

  15. Fridy, P. C. et al. Nat. Methods 11, 1253–1260 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (32150023 to P.L.), the National Key R&D Program (2019YFA0508403 and 2023YFF1204703 to P.L.), the Natural Science Foundation of Xiamen, China (3502Z20227251 to Z.L.), Xiamen Ocean and Fisheries Development Special Funds Program (22CZP006HJ03 to Z.L.).

Author information

Authors and Affiliations

  1. State Key Laboratory of Membrane Biology & Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing, China

    Wen Jia & Pilong Li

  2. Key Laboratory of Marine Genetic Resources, State Key Laboratory Breeding Base of Marine Genetic Resources, Fujian Key Laboratory of Marine Genetic Resources, Fujian Collaborative Innovation Centre for Exploitation and Utilization of Marine Biological Resources, Third Institute of Oceanography Ministry of Natural Resources, Xiamen, Fujian, China

    Weijie Li & Zengpeng Li

Authors
  1. Wen Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weijie Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zengpeng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pilong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

P.L conceived the ideas. Z.L. and P.L supervised the project. W.J. performed cell biology and biochemical experiments. W.L. performed the selection of nanobody and affinity assay. W.J. wrote the manuscript. Z.L. and P.L. edited the manuscript. All authors have commented on and approved the manuscript.

Corresponding authors

Correspondence to Zengpeng Li or Pilong Li.

Ethics declarations

Competing interests

P.L. is the scientific co-founder of NuPhase Therapeutics, whose projects are not related to this work. Other authors declare that they have no other conflict of interest.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jia, W., Li, W., Li, Z. et al. An all-in-one targeted protein degradation platform guided by degradation condensates-bridging bi-specific nanobodies. Cell Res (2024). https://doi.org/10.1038/s41422-024-00942-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41422-024-00942-3

Search

Advanced search

Quick links