PXD057810-1

PXD057810 is an original dataset announced via ProteomeXchange.

Title	Development of a p62 biodegrader for autophagy targeted degradation
Description	Harnessing autophagy for targeted degradation of intracellular cargo is a promising extension to proteasome-based targeted protein degradation because of the capacity and versatility of lysosomes, broadening the scope of therapeutic targets. First autophagy-based degraders and glues have been identified; however, it remains unclear which component of the autophagy lysosomal pathway is most efficacious to induce the selective degradation of targets when brought into proximity. Here, we describe a platform to systematically evaluate induced proximity of autophagy candidates with mitochondria using a nanobody-based and small molecule heterobifunctional dimerizer approach. We show that induced proximity of different effectors such as autophagy cargo receptors, ATG8-like proteins or the kinases ULK1 and TBK1 are sufficient to trigger degradation of mitochondria. In contrast, self-oligomerizing autophagy cargo receptors outperform ATG8-like effectors and autophagy kinases in clearing a soluble cytosolic protein. By developing an intrabody against the autophagy cargo receptor p62, one of the strongest effectors for autophagy targeted degradation, we demonstrate that recruitment of endogenous p62 with a heterobifunctional biodegrader is sufficient to clear mitochondria. This biodegrader, however, is unable to induce degradation of soluble cytosolic proteins due to its inhibitory effect on the self-oligomerization of p62. Our study highlights the importance of avidity for autophagy targeted degradation and suggests that autophagy cargo receptors are attractive entry points for the development of heterobifunctional degraders.
HostingRepository	PRIDE
AnnounceDate	2025-10-16
AnnouncementXML	Submission_2025-10-16_12:08:50.909.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Catrin Swantje Müller
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-12 13:02:59	ID requested
⏵ 1	2025-10-16 12:08:51	announced

10.1101/2024.11.19.624312;

submitter keyword: Huh7 p62 KO,Huh7

Catrin Swantje
contact affiliation	Novartis Pharma
contact email	c.s.mueller@gmx.net
lab head
Catrin Swantje Müller
contact affiliation	Novartis Pharma AG
contact email	catrin.mueller@novartis.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD057810
     1. Label: PRIDE project
     2. Name: Development of a p62 biodegrader for autophagy targeted degradation