Fig. 7. Speculative model of AUTOTAC and its mechanism-of-action.

Connecting a protein-of-interest target-binding ligand (TBL) to a p62-binding autophagy-targeting ligand (ATL) using an intermediate linker generates the chimeric AUTOTAC degrader. Recognition of the target protein occurs in tandem with the binding and activation of p62 via its ZZ domain, which is self-polymerized in complex with cargoes. Additionally, such interaction initiates a macroautophagy induction cascade in a p62-dependent manner. AUTOTACs show sustained degradative efficacy post-lysosomal degradation of the target protein, suggesting that it is recycled.