The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system

  • Nat Commun. 2022 Feb 16;13(1):904. doi: 10.1038/s41467-022-28520-4.
Chang Hoon Ji  #  1  2 ,  Hee Yeon Kim  #  1  2 ,  Min Ju Lee  #  1  2 ,  Ah Jung Heo  1  2 ,  Daniel Youngjae Park  1 ,  Sungsu Lim  3 ,  Seulgi Shin  3  4 ,  Srinivasrao Ganipisetti  5 ,  Woo Seung Yang  3 ,  Chang An Jung  2 ,  Kun Young Kim  2 ,  Eun Hye Jeong  2 ,  Sun Ho Park  2 ,  Su Bin Kim  1 ,  Su Jin Lee  1 ,  Jeong Eun Na  2 ,  Ji In Kang  6 ,  Hyung Min Chi  7 ,  Hyun Tae Kim  2 ,  Yun Kyung Kim  8  9 ,  Bo Yeon Kim  10  11 ,  Yong Tae Kwon  12  13  14
Affiliations
  • 1. Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Korea.
  • 2. AUTOTAC Bio Inc., Changkkyunggung-ro 254, Jongno-gu, Seoul, 03080, Korea.
  • 3. Convergence Research Center for Brain Science, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Korea.
  • 4. Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology (UST), Seoul, 02792, Korea.
  • 5. Brown Cancer Center, University of Louisville, 529 S Jackson Street, Louisville, KY, 40202, USA.
  • 6. Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongju, 28116, Korea.
  • 7. Department of Chemisty, Pohang University of Science and Technology, Pohang, 37673, Korea.
  • 8. Convergence Research Center for Brain Science, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Korea. [email protected].
  • 9. Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology (UST), Seoul, 02792, Korea. [email protected].
  • 10. Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongju, 28116, Korea. [email protected].
  • 11. Department of Biomolecular Science, KRIBB School, University of Science and Technology (UST), Daejeon, 34113, Korea. [email protected].
  • 12. Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Korea. [email protected].
  • 13. AUTOTAC Bio Inc., Changkkyunggung-ro 254, Jongno-gu, Seoul, 03080, Korea. [email protected].
  • 14. SNU Dementia Research Center, College of Medicine, Seoul National University, Seoul, 110-799, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 35173167 DOI: 10.1038/s41467-022-28520-4
Abstract

Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several degraders that harness the Proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux is still missing. In this study, we develop a general chemical tool and platform technology termed AUTOphagy-TArgeting Chimera (AUTOTAC), which employs bifunctional molecules composed of target-binding ligands linked to autophagy-targeting ligands. AUTOTACs bind the ZZ domain of the otherwise dormant Autophagy receptor p62/Sequestosome-1/SQSTM1, which is activated into oligomeric bodies in complex with targets for their sequestration and degradation. We use AUTOTACs to degrade various oncoproteins and degradation-resistant aggregates in neurodegeneration at nanomolar DC50 values in vitro and in vivo. AUTOTAC provides a platform for selective proteolysis in basic research and drug development.

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