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Annals of the New York Academy of Sciences
04, 2022;1510 (1): 79-99.

Targeted protein degradation: from small molecules to complex organelles-a Keystone Symposia report.

Jennifer Cable, Eilika Weber-Ban, Tim Clausen, Kylie J Walters, Michal Sharon, Daniel J Finley, Yangnan Gu, John Hanna, Yue Feng, Sascha Martens, Anne Simonsen, Malene Hansen, Hong Zhang, Jonathan M Goodwin, Alessio Reggio, Chunmei Chang, Liang Ge, Brenda A Schulman, Raymond J Deshaies, Ivan Dikic, J Wade Harper, Ingrid E Wertz, Nicolas H Thomä, Mikołaj Słabicki, Judith Frydman, Ursula Jakob, Della C David, Eric J Bennett, Carolyn R Bertozzi, Richa Sardana, Vinay V Eapen, Serena Carra
Author Information
  1. Jennifer Cable: PhD Science Writer, New York, New York.
  2. Eilika Weber-Ban: Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.
  3. Tim Clausen: Research Institute of Molecular Pathology (IMP), Vienna BioCenter and Medical University of Vienna, Vienna, Austria.
  4. Kylie J Walters: Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
  5. Michal Sharon: Department of Bimolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
  6. Daniel J Finley: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
  7. Yangnan Gu: Department of Plant and Microbial Biology and Innovative Genomics Institute, University of California, Berkeley, California.
  8. John Hanna: Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.
  9. Yue Feng: Princess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  10. Sascha Martens: Max Perutz Labs, University of Vienna, Vienna BioCenter (VBC), Vienna, Austria.
  11. Anne Simonsen: Department of Molecular Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  12. Malene Hansen: Sanford Burnham Prebys Medical Discovery Institute, Program of Development, Aging, and Regeneration, La Jolla, California.
  13. Hong Zhang: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences and College of Life Sciences, University of Chinese Academy of Sciences, Beijing, People's Republic of China.
  14. Jonathan M Goodwin: Casma Therapeutics, Cambridge, Massachusetts.
  15. Alessio Reggio: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
  16. Chunmei Chang: Molecular and Cell Biology, University of California, Berkeley, Berkeley, California.
  17. Liang Ge: State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
  18. Brenda A Schulman: Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
  19. Raymond J Deshaies: Amgen, Inc., Thousand Oaks, California.
  20. Ivan Dikic: Institute of Biochemistry II, School of Medicine and Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt, Germany.
  21. J Wade Harper: Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts.
  22. Ingrid E Wertz: Departments of Molecular Oncology and Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California.
  23. Nicolas H Thomä: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  24. Mikołaj Słabicki: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  25. Judith Frydman: Biophysics Graduate Program, Department of Biology and Department of Genetics, Stanford University, Stanford, California.
  26. Ursula Jakob: Department of Molecular, Cellular and Developmental Biology, College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan.
  27. Della C David: German Center for Neurodegenerative Diseases (DZNE), and Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
  28. Eric J Bennett: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, California.
  29. Carolyn R Bertozzi: Department of Chemistry and Stanford ChEM-H, Stanford University and Howard Hughes Medical Institute, Stanford, California.
  30. Richa Sardana: Weill Institute of Cell and Molecular Biology and Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York.
  31. Vinay V Eapen: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
  32. Serena Carra: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
PMID: 35000205 DOI: 10.1111/nyas.14745

Abstract

Targeted protein degradation is critical for proper cellular function and development. Protein degradation pathways, such as the ubiquitin proteasomes system, autophagy, and endosome-lysosome pathway, must be tightly regulated to ensure proper elimination of misfolded and aggregated proteins and regulate changing protein levels during cellular differentiation, while ensuring that normal proteins remain unscathed. Protein degradation pathways have also garnered interest as a means to selectively eliminate target proteins that may be difficult to inhibit via other mechanisms. On June 7 and 8, 2021, several experts in protein degradation pathways met virtually for the Keystone eSymposium "Targeting protein degradation: from small molecules to complex organelles." The event brought together researchers working in different protein degradation pathways in an effort to begin to develop a holistic, integrated vision of protein degradation that incorporates all the major pathways to understand how changes in them can lead to disease pathology and, alternatively, how they can be leveraged for novel therapeutics.

Keywords

aggregation autophagy lysophagy proteasome protein degradation ubiquitin

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Grants

  1. R01 GM144367/NIGMS NIH HHS
  2. R21 AG046799/NIA NIH HHS
  3. R35 GM122506/NIGMS NIH HHS
  4. W 1261/Austrian Science Fund FWF

MeSH Term

Autophagy
Humans
Organelles
Proteasome Endopeptidase Complex
Proteins
Proteolysis
Ubiquitin

Chemicals

Proteins
Ubiquitin
Proteasome Endopeptidase Complex
Journal Article Research Support, N.I.H., Extramural
Article has an altmetric score of 12

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