PXD037899

PXD037899 is an original dataset announced via ProteomeXchange.

Dataset Summary

Title	Cellular determinants of targeted membrane protein degradation by lysosome targeting chimeras
Description	Targeted protein degradation is a powerful therapeutic strategy that offers benefits over canonical target inhibition. Lysosome targeting chimeras (LYTACs) harness lysosome trafficking receptors such as the cation-independent mannose-6-phosphate receptor (CI-M6PR) to direct secreted and membrane proteins to lysosomes. Their development as therapeutics would benefit from mechanistic insights into the factors that govern their activity. We conducted a genome-wide CRISPR screen to identify modulators of LYTAC-mediated membrane protein degradation. Disrupting retromer genes improved LYTAC-induced degradation by reducing the recycling of LYTAC-CI-M6PR complexes from endosomes to the plasma membrane. We identified neddylated cullin 3 as a predictive marker for LYTAC efficacy. Quantitative proteomics revealed that a significant fraction of cell-surface CI-M6PR remains occupied by endogenous M6P-modified glycoproteins. Accordingly, disruption of M6P biosynthesis enhanced the internalization of LYTAC-target complexes. Our findings inform new design strategies for LYTACs with enhanced degradation activity and elucidate the biology of CI-M6PR with implications for enzyme replacement therapies.
HostingRepository	PRIDE
AnnounceDate	2024-01-26
AnnouncementXML	Submission_2024-01-26_07:02:18.365.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Nicholas Riley
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Dataset History

Revision	Datetime	Status	ChangeLog Entry
0	2022-11-03 04:10:12	ID requested
⏵ 1	2024-01-26 07:02:19	announced

Publication List

Ahn G, Riley NM, Kamber RA, Wisnovsky S, Moncayo von Hase S, Bassik MC, Banik SM, Bertozzi CR, Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras. Science, 382(6668):eadf6249(2023) [pubmed]
10.1126/science.adf6249;

Ahn G, Riley NM, Kamber RA, Wisnovsky S, Moncayo von Hase S, Bassik MC, Banik SM, Bertozzi CR, Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras. Science, 382(6668):eadf6249(2023) [pubmed]

10.1126/science.adf6249;

Keyword List

submitter keyword: DIA, LYTAC, quantitative proteomics,lysosome, CRISPRi

submitter keyword: DIA, LYTAC, quantitative proteomics,lysosome, CRISPRi

Contact List

Carolyn Bertozzi
contact affiliation	Department of Chemistry and Sarafan ChEM-H
contact email	bertozzi@stanford.edu
lab head
Nicholas Riley
contact affiliation	Stanford University
contact email	riley.nicholasm@gmail.com
dataset submitter

Full Dataset Link List

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/2024/01/PXD037899
PRIDE project URI

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/2024/01/PXD037899

PRIDE project URI

Repository Record List

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