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

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.

Targeted protein degradation: mechanisms, strategies and application

“…Such a conformation change exposes the LIR motif of p62, and prmotes its interaction with LC3 on the autophagic membrane. Ji et al designed the AUTOphagy-TArgeting Chimera (AUTOTAC) platform that bypasses the requirement of ubiquitin 80 (Fig. 11 ).…”

“…AUTOTAC molecules consist of a module that interacts with the ZZ domain of p62, and a POI-targeting module. 80 The addition of AUTOTAC molecules bridges the POI and p62, independent of ubiquitin on the POI. AUTOTAC promotes the oligomerization and activation of p62, leading to the degradation of the POI by the autophagy–lysosome pathway (Fig.…”

“…Using murine models expressing human pathological tau mutants, Ji et al demonstrated the AUTOTAC could effectively remove misfolded tau. 80 In contrast, the proteasome-based technologies, such as PROTAC and molecular glue, are usually ineffective in dealing with the misfolded proteins. In addition to Tau, AUTOTACs could also efficiently remove multiple oncoproteins, such as degrading androgen receptor (AR).…”

“…In addition to Tau, AUTOTACs could also efficiently remove multiple oncoproteins, such as degrading androgen receptor (AR). 80 …”

“…With the intensive research in the endosome-lysosome and autophagosome-lysosome degradation pathways, TPD strategies via the lysosomal pathway, such as LYTAC, AbTAC, ATTEC, AUTAC, bispecific aptamer chimeras, and AUTOTAC have emerged in recent years 39 , 79 , 80 (Fig. 6 and Table 1 ).…”