PXD057365

PXD057365 is an original dataset announced via ProteomeXchange.

Title	Morphological and genetic screens reveal mechanisms of BiDAC-induced plasma membrane protein degradation
Description	The discovery of bifunctional degradation activating compounds (BiDACs) has led to the development of a new class of drugs that promote the clearance of their protein targets. BiDAC-induced ubiquitination is generally believed to direct cytosolic and nuclear proteins to proteolytic destruction by proteasomes. However, pathways that govern the degradation of other classes of BiDAC targets, such as integral membrane and intraorganellar proteins, have not been investigated in depth. In this study we used morphological profiling and CRISPR/Cas9 genetic screens to investigate the mechanisms by which BiDACs induce the degradation of plasma membrane receptor tyrosine kinases (RTKs) EGFR and Her2. We found that BiDAC-dependent ubiquitination triggers the trafficking of RTKs from the plasma membrane to lysosomes for degradation. Surprisingly, functional proteasomes were required for endocytosis of RTKs upstream of the lysosome. Additionally, our screen uncovered a non-canonical function of the lysosome-associated arginine/lysine transporter PQLC2 in EGFR degradation. Our data show that BiDACs may target proteins to proteolytic machinery other than the proteasome and motivate further investigation of mechanisms that govern the degradation of diverse classes of BiDAC targets.
HostingRepository	PRIDE
AnnounceDate	2025-05-11
AnnouncementXML	Submission_2025-05-10_17:05:07.072.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Niclas Olsson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-30 11:46:36	ID requested
⏵ 1	2025-05-10 17:05:07	announced

10.1038/s41467-025-59627-z;

Villa S, Jafri Q, Lazzari-Dean JR, Sangha M, Olsson N, Lefebvre AEYT, Fitzgerald ME, Jackson K, Chen Z, Feng BY, Nile AH, Stokoe D, Bersuker K, BiDAC-dependent degradation of plasma membrane proteins by the endolysosomal system. Nat Commun, 16(1):4345(2025) [pubmed]

submitter keyword: Human, LC-MSMS, AP-MS, Q Exactive

David Stokoe
contact affiliation	Calico Life Sciences
contact email	dhstokoe@calicolabs.com
lab head
Niclas Olsson
contact affiliation	Calico Life Sciences
contact email	niclas@calicolabs.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/05/PXD057365

PRIDE project URI

• PRIDE
  1. PXD057365
     1. Label: PRIDE project
     2. Name: Morphological and genetic screens reveal mechanisms of BiDAC-induced plasma membrane protein degradation