CBL ubiquitin ligase targets translation as a degrader E3

Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional molecules that recruit 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 utilised 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 in cells and in <i>in vitro</i> reconstituted assays. We further developed peptidic PROTACs, termed eIFTerminators, by linking CBLock to an eIF4E-binding peptide. Among them, eIFTerminator4 rapidly eliminates endogenous eIF4E <i>via</i> both lysosomal and proteasomal pathways. Unexpectedly, eIFTerminator4 also caused a decrease in eIF4A and eIF4G levels, leading to a reduction in overall protein translation in 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 combating challenging drug targets.