PXD063494

PXD063494 is an original dataset announced via ProteomeXchange.

Title	CBL ubiquitin ligase targets translation as a degrader E3
Description	Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional molecules that recruits an ubiquitin ligase (E3) and a neo-substrate into a ternary complex, enabling selective protein degradation. Despite the presence of over 600 E3s, only a handful are utilized in PROTAC application, potentially limiting the number of druggable targets. Here, we investigate whether Casitas B-cell lymphoma (CBL) can be harnessed as a degrader E3 to promote ubiquitination and degradation of the eukaryotic translation initiation factor 4E (eIF4E). Using a selective CBL binding peptide, CBLock, we demonstrate that CBL facilitates the ubiquitination of CBLock-eIF4E fusion both in vitro and in cells. We further developed peptidic PROTACs, termed eIFTerminators, by linking CBLock to an eIF4E-binding peptide. Among them, eIFTerminator4 was found to rapidly eliminate endogenous eIF4E via both lysosomal and proteasomal pathways. Additionally, eIF4E depletion was found to be associated with a reduction in eIF4A1 and eIF4G1 levels, thereby disrupting translation in cancer cells. Our findings establish proof-of-concept that CBL can function as a degrader E3, expanding the arsenal of E3s available for targeted protein degradation in combatting challenging drug targets.
HostingRepository	PRIDE
AnnounceDate	2026-01-19
AnnouncementXML	Submission_2026-01-18_16:11:52.189.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sergio Lilla
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Escherichia coli; NCBI TaxID: NEWT:562; scientific name: Bacteria; NCBI TaxID: NCBITaxon:2;
ModificationList	ubiquitination signature dipeptidyl lysine
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-30 05:12:58	ID requested
⏵ 1	2026-01-18 16:11:53	announced

Wicks AT, Buetow L, Suzuki T, Schmidt T, Lilla S, Macmillan-Jones A, Turney J, Gohlke A, Bushell M, Hock AK, Huang DT, CBL ubiquitin ligase targets translation as a degrader E3. Chem Sci, ():(2025) [pubmed]

10.1039/d5sc06141e;

submitter keyword: CBL,PROTAC, Targeted protein Degradation, ubiquitin, mRNA, translation, eIF4E

Danny Huang
contact affiliation	Cancer Research UK Scotland Institute (Formerly the Cancer Research UK Beatson Institute) Garscube Estate Switchback Road Bearsden Glasgow, G61 1BD
contact email	d.huang@crukscotlandinstitute.ac.uk
lab head
Sergio Lilla
contact affiliation	Proteomics
contact email	s.lilla@beatson.gla.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD063494
     1. Label: PRIDE project
     2. Name: CBL ubiquitin ligase targets translation as a degrader E3