Caspase-8 Inhibition Prevents the Cleavage and Degradation of E3 Ligase Substrate Receptor Cereblon and Potentiates Its Biological Function

ABSTRACT: Cereblon (CRBN), a substrate receptor of cullin 4-RING E3 ligase (CRL4), mediates the ubiquitination and degradation of constitutive substrates and immunomodulatory drug-induced neo-substrates including MEIS2, c-Jun, CLC1, IKZF1/3, CK1α, and SALL4. It has been reported that CRBN itself could be degraded through the ubiquitin-proteasome system by its associated or other cullin-RING E3 ligases, thus influencing its biological functions. However, it is unknown whether the CRBN stability and its biological function could be modulated by caspases. In this study, using model cell lines, we found that activation of the death receptor using tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) leads to the decreased CRBN protein level. Through pharmacological inhibition and activation of

SUBMITTER: Zhou L 

PROVIDER: S-EPMC7773819 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature