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

Chang Hoon Ji, Hee Yeon Kim, Min Ju Lee, Ah Jung Heo, Daniel Youngjae Park, Sungsu Lim, Seulgi Shin, Srinivasrao Ganipisetti, Woo Seung Yang, Chang An Jung, Kun Young Kim, Eun Hye Jeong, Sun Ho Park, Su Kim, Su Jin Lee, Jeong Eun Na, Ji In Kang, Hyung Min Chi, Hyun Tae Kim, Yun Kyung Kim (), Bo Yeon Kim () and Yong Tae Kwon ()
Additional contact information
Chang Hoon Ji: Seoul National University
Hee Yeon Kim: Seoul National University
Min Ju Lee: Seoul National University
Ah Jung Heo: Seoul National University
Daniel Youngjae Park: Seoul National University
Sungsu Lim: Korea Institute of Science and Technology (KIST)
Seulgi Shin: Korea Institute of Science and Technology (KIST)
Srinivasrao Ganipisetti: Brown Cancer Center, University of Louisville
Woo Seung Yang: Korea Institute of Science and Technology (KIST)
Chang An Jung: AUTOTAC Bio Inc.
Kun Young Kim: AUTOTAC Bio Inc.
Eun Hye Jeong: AUTOTAC Bio Inc.
Sun Ho Park: AUTOTAC Bio Inc.
Su Kim: Seoul National University
Su Jin Lee: Seoul National University
Jeong Eun Na: AUTOTAC Bio Inc.
Ji In Kang: Korea Research Institute of Bioscience and Biotechnology, Ochang
Hyung Min Chi: Pohang University of Science and Technology
Hyun Tae Kim: AUTOTAC Bio Inc.
Yun Kyung Kim: Korea Institute of Science and Technology (KIST)
Bo Yeon Kim: Korea Research Institute of Bioscience and Biotechnology, Ochang
Yong Tae Kwon: Seoul National University

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28520-4

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