PXD058514 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Development of polyvalent folate receptor-targeting chimeras (FRTACs) for lysosomal degradation of membrane proteins |
Description | Lysosome-targeting chimeras (LYTACs) have emerged as a revolutionary targeted protein degradation (TPD) technology in modulating the levels of extracellular and membrane proteins. However, lack of lysosome-trafficking receptors (LTRs) limits the development of LYTACs. Here, we firstly confirm that folate receptor α (FRα) is a new generation of lysosome-targeting receptor (LTR) of LYTAC, facilitating the transport of membrane proteins to lysosomes to realize degradation. Moreover, novel FRTACs are constructed by a new “polyvalent crosslinking strategy”, instead of the traditional “one folate conjugating one drug strategy”. Polyvalency creates avidity, allowing FRTACs crosslinking FRα to dramatically improve the degradation efficiency. As a result, the optimized FRTACs, including EGFR-targeting FR-Ctx, PD-L1-targeting FR-Atz, TROP2-targeting FR-Stz, and HER2-targeting FR-Ttz, successfully eliminate cell surface targets with a subnanomole activity. Mechanism investigation reveals that FRTACs trigger targets degradation in a FRα- and lysosomal-dependent manner. Besides, FR-Ctx reduces cancer cell proliferation, and FR-Atz increases the cytotoxicity of T cells toward tumor cells. Furthermore, FR-Atz exhibits potent degradation efficiency of PD-L1 in vivo and elicits tumor-specific immune responses by switching the tumor immune microenvironment from a suppressed state to an activated state in both RM-1 mice model and humanized PD-1/PD-L1 B16F10 mice model. To our knowledge, FRTACs are the most potent protein degrader ever reported. The novel FRTACs will expand the application of FRα and provide a new platform for designing tumor-targeting LYTACs. |
HostingRepository | PRIDE |
AnnounceDate | 2025-05-30 |
AnnouncementXML | Submission_2025-05-30_02:27:54.607.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Dian Xiao |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | No PTMs are included in the dataset |
Instrument | Q Exactive HF |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2024-12-03 01:10:23 | ID requested | |
⏵ 1 | 2025-05-30 02:27:55 | announced | |
Publication List
Keyword List
submitter keyword: lysosome-targeting chimeras, polyvalent strategy,targeted protein degradation, folate receptor |
Contact List
Dian Xiao |
contact affiliation | National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China |
contact email | be_xiaodian@163.com |
lab head | |
Dian Xiao |
contact affiliation | National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology |
contact email | be_xiaodian@163.com |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD058514
- Label: PRIDE project
- Name: Development of polyvalent folate receptor-targeting chimeras (FRTACs) for lysosomal degradation of membrane proteins