# CBL ubiquitin ligase targets translation as a degrader E3

## TL;DR

Researchers developed a new PROTAC using the CBL ubiquitin ligase to degrade eIF4E, disrupting protein translation and expanding options for targeting hard-to-drug proteins.

## Contribution

The study demonstrates CBL's novel use as a degrader E3 ligase in PROTACs for targeted protein degradation.

## Key findings

- CBLock peptide enables CBL-mediated ubiquitination and degradation of eIF4E in cells and in vitro.
- eIFTerminator4, a peptidic PROTAC, degrades endogenous eIF4E via lysosomal and proteasomal pathways.
- eIFTerminator4 also reduces eIF4A and eIF4G levels, impairing overall protein translation.

## Abstract

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 in vitro reconstituted assays. We further developed peptidic PROTACs, termed eIFTerminators, by linking CBLock to an eIF4E-binding peptide. Among them, eIFTerminator4 rapidly eliminates endogenous eIF4E via 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.

The peptidic PROTAC elFTerminator brings CBL and elF4E together and promotes CBL-mediated elF4E degradation. Consequently, protein translation is disrupted.