CBL ubiquitin ligase targets translation as a degrader E3

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Escherichia Coli Bacteria

DISEASE(S): Disease Free

SUBMITTER: Sergio Lilla  

LAB HEAD: Danny Huang

PROVIDER: PXD063494 | Pride | 2026-01-19

REPOSITORIES: Pride