The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35173167.
- Also identified by DOI 10.1038/s41467-022-28520-4 and PMC identifier 8850458.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 DC<sub>50</sub> values in vitro and in vivo. AUTOTAC provides a platform for selective proteolysis in basic research and drug development.
Medical subject headings
- Autophagy
- Lysosomes
- Oncogene Proteins
- Protein Aggregates
- Proteolysis