Targeted protein degradation via the autophagy-lysosome system: AUTOTAC (AUTOphagy-TArgeting Chimera). Issue 9 (2nd September 2022)

• Record Type: Journal Article
• Authors: Ji, Chang Hoon; Lee, Min Ju; Kim, Hee Yeon; Heo, Ah Jung; Park, Daniel Youngjae; Kim, Yun Kyung; Kim, Bo Yeon; Kwon, Yong Tae
• Is Part Of: Autophagy. Volume 18:Issue 9(2022)
• Page Start: 2259
• Page End: 2262
• Publication Date: 2022-09-02
• Subjects: Chemical tools -- selective autophagy -- protein quality control -- proteolysis -- N-degron pathway -- N-terminal arginylation -- SQSTM1/p62 -- targeted protein degradation (TPD) -- neurodegeneration -- proteinopathy; Autophagic vacuoles -- Periodicals; Apoptosis -- Periodicals; Cell death -- Periodicals; Lysosomes -- Periodicals; Degeneration (Pathology) -- Periodicals; Autophagy -- Periodicals; Cell Death -- Periodicals; Lysosomes -- Periodicals; Periodicals; 571.936
• DOI: 10.1080/15548627.2022.2091338
• Languages: English
• ISSNs: 1554-8627

Abstract

ABSTRACT: Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several types of degraders that harness the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux remains unavailable. In this study, we developed a general chemical tool by which given intracellular proteins are targeted to macroautophagy for lysosomal degradation. This platform technology, termed AUTOTAC (AUTOphagy-TArgeting Chimera), employs bifunctional molecules composed of target-binding ligands (TBLs) linked to autophagy-targeting ligands (ATLs). Upon binding to targets via the TBL, the ATL binds the ZZ domain of the otherwise dormant autophagy receptor SQSTM1/p62 (sequestosome 1), which activates SQSTM1 associated with targets and sequesters them into oligomeric species for autophagic targeting and lysosomal degradation. AUTOTACs were used to degrade various oncoproteins or aggregation-prone proteins in neurodegeneration both in vitro and/or in vivo . We suggest that AUTOTAC provides a platform for selective proteolysis as a research tool and in drug development.