Figure 13.

Concepts of degrader technologies hijacking autophagy pathways. (a) AUTACs bind to the POI and attach a degradation tag mimicking S-guanylation, a posttranslational modification that triggers K63 ubiquitination of the POI. The POI is recognized by the autophagy receptor SQSTM1/p62 and is recruited to the selective autophagy pathway for depletion. (b) ATTECs interact with both the POI and LC3, tethering the POI to the phagophores or autophagosomes for subsequent autophagic degradation. (c) The central mode of action in AUTOTAC is the ability of the p62-binding ligand to induce a conformational activation of otherwise inactive p62 into an autophagy-compatible version. Upon binding to the p62 moiety, p62 exposes PB1 and LIR domains, promoting p62 self-polymerization in complex with targets and its interaction with LC3 on autophagic membranes. (d) The CMA-based degrader first enters the cell, then binds the target protein via the POI binding sequence and is then transported to the lysosome for degradation. POI: protein of interest; Ub: ubiquitin.