Development of a p62 biodegrader for autophagy targeted degradation

Zacharias Thiel (), David Marcellin, Carole Manneville, Benedikt Goretzki, Luca Egger, Rob Maher, Noémie Siccardi, Laura Torres, Alexandra Probst, Catrin S. Müller, Nathalie George, Markus Vogel, Sabine Sinterhauf, Alexandra Lavoisier, Ji-Young Choi, Laurianne Forcellino, Alexandro Landshammer, Patrick Hauck, Celine Be, Frédéric Villard, Sascha Gutmann, Marc Meyer, Felix Freuler, Alexandra Hinniger, César Fernández, Suzanne Chau, Maude Patoor, Gilles Sansig, Gabriel Mitchell and Beat Nyfeler ()
Additional contact information
Zacharias Thiel: Novartis, Discovery Sciences, Biomedical Research
David Marcellin: Novartis, Discovery Sciences, Biomedical Research
Carole Manneville: Novartis, Discovery Sciences, Biomedical Research
Benedikt Goretzki: Novartis, Discovery Sciences, Biomedical Research
Luca Egger: Novartis, Discovery Sciences, Biomedical Research
Rob Maher: Novartis, Discovery Sciences, Biomedical Research
Noémie Siccardi: Novartis, Discovery Sciences, Biomedical Research
Laura Torres: Novartis, Open Innovation at Global Health Disease Area, Biomedical Research
Alexandra Probst: Novartis, Global Health Disease Area, Biomedical Research
Catrin S. Müller: Novartis, Discovery Sciences, Biomedical Research
Nathalie George: Novartis, Biologics Research Center, Biomedical Research
Markus Vogel: Novartis, Biologics Research Center, Biomedical Research
Sabine Sinterhauf: Novartis, Biologics Research Center, Biomedical Research
Alexandra Lavoisier: Novartis, Biologics Research Center, Biomedical Research
Ji-Young Choi: Novartis, Biologics Research Center, Biomedical Research
Laurianne Forcellino: Novartis, Biologics Research Center, Biomedical Research
Alexandro Landshammer: Novartis, Disease Area X, Biomedical Research
Patrick Hauck: Novartis, Discovery Sciences, Biomedical Research
Celine Be: Novartis, Discovery Sciences, Biomedical Research
Frédéric Villard: Novartis, Discovery Sciences, Biomedical Research
Sascha Gutmann: Novartis, Discovery Sciences, Biomedical Research
Marc Meyer: Novartis, Discovery Sciences, Biomedical Research
Felix Freuler: Novartis, Discovery Sciences, Biomedical Research
Alexandra Hinniger: Novartis, Discovery Sciences, Biomedical Research
César Fernández: Novartis, Discovery Sciences, Biomedical Research
Suzanne Chau: Novartis, Discovery Sciences, Biomedical Research
Maude Patoor: Novartis, Discovery Sciences, Biomedical Research
Gilles Sansig: Novartis, Discovery Sciences, Biomedical Research
Gabriel Mitchell: Novartis, Open Innovation at Global Health Disease Area, Biomedical Research
Beat Nyfeler: Novartis, Discovery Sciences, Biomedical Research

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Autophagy-based targeted degradation offers a powerful complement to proteasomal degradation leveraging the capacity and versatility of lysosomes to degrade complex cargo. However, it remains unclear which components of the autophagy-lysosomal pathway are most effective for targeted degradation. Here, we describe two orthogonal induced-proximity strategies to identify autophagy effectors capable of degrading organelles and soluble targets. Recruitment of autophagy cargo receptors, ATG8-like proteins, or the kinases ULK1 and TBK1 is sufficient to trigger mitophagy, while only autophagy cargo receptors capable of self-oligomerization degrade soluble cytosolic proteins. We further report a single-domain antibody against p62 and its use as a heterobifunctional degrader to clear mitochondria. Fusing the p62 single-domain antibody to PINK1 enables selective targeting of damaged mitochondria. Our study highlights the importance of avidity for targeted autophagy and suggests that autophagy cargo receptors are attractive entry points for the development of heterobifunctional degraders for organelles or protein aggregates.

Date: 2025
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DOI: 10.1038/s41467-025-65868-9

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