Thiel, Zacharias, Marcellin, David, Manneville, Carole, Goretzki, Benedikt, Egger, Luca, Maher, Rob, Siccardi, Noemie, Sansig, Gilles, Torres, Laura-1, Probst, Alexandra, Müller, Catrin, Landshammer, Alexandro, George, Nathalie, Vogel, Markus, Sinterhauf, Sabine, Lavoisier, Alexandra, Choi, Ji-Young, Forcellino, Laurianne, Hauck, Patrick-1, Be, Celine, Villard, Frederic, Gutmann, Sascha, Meyer, Marc, Freuler, Felix, Hinniger, Alexandra, Fernandez, Cesar, Chau, Suzanne, Patoor, Maude, Mitchell, Gabriel and Nyfeler, Beat (2025) Development of a p62 biodegrader for autophagy 1 targeted degradation. Nature communications, 16 (10858).

Abstract

Harnessing autophagy for targeted degradation is a promising extension to proteasome-based 20 targeted protein degradation because of the capacity and versatility of lysosomes to degrade large and 21 complex cargo, thus broadening the scope of therapeutic targets. While small-molecule degraders 22 recruiting the autophagy machinery to targets are starting to emerge, it remains unclear which component 23 of the autophagy lysosomal pathway is most efficacious to induce selective target degradation. Here, we 24 describe two orthogonal induced-proximity strategies to identify and prioritize autophagy effectors that are 25 sufficient to degrade organelles as well as soluble targets. We show that induced proximity of different 26 effectors such as autophagy cargo receptors, ATG8-like proteins or the kinases ULK1 and TBK1 are 27 sufficient to trigger mitophagy. In contrast, self-oligomerizing autophagy cargo receptors outperform ATG8-28 like effectors and autophagy-related kinases in clearing a soluble cytosolic protein. We further explore the 29 importance of avidity for targeted degradation via autophagy and reveal that the PB1 domain of p62 fused 30 to a LIR peptide is a minimal degron to induce the degradation of mitochondria as well as cytosolic proteins. 31 By developing a novel and highly selective intrabody against the autophagy cargo receptor p62 into a 32 heterobifunctional degrader, we demonstrate that recruitment of endogenous p62 is sufficient to clear 33 mitochondria. We then fused the p62 intrabody to PINK1 to selectively direct this biodegrader to damaged 34 mitochondria and induce mitophagy. Our study highlights the importance of avidity and suggests that 35 autophagy cargo receptors are attractive entry points for the development of heterobifunctional degraders 36 for complex targets such as organelles or protein aggregates.

Item Type:	Article
Date Deposited:	07 Apr 2026 00:45
Last Modified:	07 Apr 2026 00:45
URI:	https://oak.novartis.com/id/eprint/57492