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

Jennifer Cable¹, Eilika Weber-Ban², Tim Clausen³, Kylie J Walters⁴, Michal Sharon⁵, Daniel J Finley⁶, Yangnan Gu⁷, John Hanna⁸, Yue Feng⁹, Sascha Martens¹⁰, Anne Simonsen^{11

12}, Malene Hansen¹³, Hong Zhang¹⁴, Jonathan M Goodwin¹⁵, Alessio Reggio¹⁶, Chunmei Chang¹⁷, Liang Ge¹⁸, Brenda A Schulman¹⁹, Raymond J Deshaies²⁰, Ivan Dikic²¹, J Wade Harper²², Ingrid E Wertz^{23

24}, Nicolas H Thomä²⁵, Mikołaj Słabicki^{26

27

28}, Judith Frydman^{29

30

31}, Ursula Jakob³², Della C David³³, Eric J Bennett³⁴, Carolyn R Bertozzi³⁵, Richa Sardana³⁶, Vinay V Eapen⁶, Serena Carra³⁷

Affiliations

¹ PhD Science Writer, New York, New York.
² Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.
³ Research Institute of Molecular Pathology (IMP), Vienna BioCenter and Medical University of Vienna, Vienna, Austria.
⁴ Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
⁵ Department of Bimolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
⁶ Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
⁷ Department of Plant and Microbial Biology and Innovative Genomics Institute, University of California, Berkeley, California.
⁸ Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.
⁹ Princess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Max Perutz Labs, University of Vienna, Vienna BioCenter (VBC), Vienna, Austria.
¹¹ 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 Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
¹³ Sanford Burnham Prebys Medical Discovery Institute, Program of Development, Aging, and Regeneration, La Jolla, California.
¹⁴ 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.
¹⁵ Casma Therapeutics, Cambridge, Massachusetts.
¹⁶ Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
¹⁷ Molecular and Cell Biology, University of California, Berkeley, Berkeley, California.
¹⁸ State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
¹⁹ Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
²⁰ Amgen, Inc., Thousand Oaks, California.
²¹ Institute of Biochemistry II, School of Medicine and Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt, Germany.
²² Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts.
²³ Departments of Molecular Oncology and Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California.
²⁴ Bristol Myers Squibb, Brisbane, California.
²⁵ Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
²⁶ Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
²⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
²⁸ Division of Translational Medical Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²⁹ Biophysics Graduate Program, Department of Biology and Department of Genetics, Stanford University, Stanford, California.
³⁰ Biohub, San Francisco, California.
³¹ Division of CryoEM and Bioimaging, SSRL, SLAC National Accelerator Laboratory, Menlo Park, California.
³² Department of Molecular, Cellular and Developmental Biology, College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan.
³³ German Center for Neurodegenerative Diseases (DZNE), and Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
³⁴ Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, California.
³⁵ Department of Chemistry and Stanford ChEM-H, Stanford University and Howard Hughes Medical Institute, Stanford, California.
³⁶ Weill Institute of Cell and Molecular Biology and Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York.
³⁷ Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

PMID: 35000205
DOI: 10.1111/nyas.14745

Free article

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

Jennifer Cable et al. Ann N Y Acad Sci. 2022 Apr.

Free article

. 2022 Apr;1510(1):79-99.

doi: 10.1111/nyas.14745. Epub 2022 Jan 8.

Authors

Affiliations

¹ PhD Science Writer, New York, New York.
² Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.
³ Research Institute of Molecular Pathology (IMP), Vienna BioCenter and Medical University of Vienna, Vienna, Austria.
⁴ Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
⁵ Department of Bimolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
⁶ Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
⁷ Department of Plant and Microbial Biology and Innovative Genomics Institute, University of California, Berkeley, California.
⁸ Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.
⁹ Princess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Max Perutz Labs, University of Vienna, Vienna BioCenter (VBC), Vienna, Austria.
¹¹ 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 Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
¹³ Sanford Burnham Prebys Medical Discovery Institute, Program of Development, Aging, and Regeneration, La Jolla, California.
¹⁴ 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.
¹⁵ Casma Therapeutics, Cambridge, Massachusetts.
¹⁶ Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
¹⁷ Molecular and Cell Biology, University of California, Berkeley, Berkeley, California.
¹⁸ State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
¹⁹ Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
²⁰ Amgen, Inc., Thousand Oaks, California.
²¹ Institute of Biochemistry II, School of Medicine and Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt, Germany.
²² Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts.
²³ Departments of Molecular Oncology and Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California.
²⁴ Bristol Myers Squibb, Brisbane, California.
²⁵ Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
²⁶ Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
²⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
²⁸ Division of Translational Medical Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²⁹ Biophysics Graduate Program, Department of Biology and Department of Genetics, Stanford University, Stanford, California.
³⁰ Biohub, San Francisco, California.
³¹ Division of CryoEM and Bioimaging, SSRL, SLAC National Accelerator Laboratory, Menlo Park, California.
³² Department of Molecular, Cellular and Developmental Biology, College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan.
³³ German Center for Neurodegenerative Diseases (DZNE), and Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
³⁴ Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, California.
³⁵ Department of Chemistry and Stanford ChEM-H, Stanford University and Howard Hughes Medical Institute, Stanford, California.
³⁶ Weill Institute of Cell and Molecular Biology and Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York.
³⁷ 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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References

1. Chen, B., M. Retzlaff, T. Roos, et al. 2011. Cellular strategies of protein quality control. Cold Spring Harb. Perspect. Biol. 3: a004374.
1. Labbadia, J. & R.I. Morimoto. 2015. The biology of proteostasis in aging and disease. Annu. Rev. Biochem. 84: 435-464.
1. Vinchi, F. 2018. Erythroid differentiation: a matter of proteome remodeling. Hemasphere 2: e26.
1. Harper, J.W. & B.A. Schulman. 2021. Cullin-ring ubiquitin ligase regulatory circuits: a quarter century beyond the F-box hypothesis. Annu. Rev. Biochem. 90: 403-429.
1. Nguyen, H.C., W. Wang & Y. Xiong. 2017. Cullin-RING E3 ubiquitin ligases: bridges to destruction. Subcell. Biochem. 83: 323-347.

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

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

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