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

Frontiers in Cell and Developmental Biology

Ruben Niesvizky¹  David S. Jayabalan¹  Xiangao Huang²  Samie R. Jaffrey³  Wenjun Yu⁴  Liang Zhou⁴  Guoqiang Xu⁴ 

[1] Department of Medicine, Weill Cornell Medicine, New York, NY, United States;Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, United States;Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States;Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, China;

关键词: cereblon;    caspase-8;    cleavage;    TRAIL;    multiple myeloma;    lenalidomide;   

DOI  :  10.3389/fcell.2020.605989

来源: DOAJ

【 摘 要 】

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 caspase-8 (CASP-8), we disclosed that CASP-8 regulates CRBN cleavage in cell lines. Site mapping experiments revealed that CRBN is cleaved after Asp9 upon CASP-8 activation, resulting in the reduced stability. Using myeloma as a model system, we further revealed that either inhibition or genetic depletion of CASP-8 enhances the anti-myeloma activity of lenalidomide (Len) by impairing CRBN cleavage, leading to the attenuated IKZF1 and IKZF3 protein levels and the reduced viability of myeloma cell lines and primary myeloma cells from patients. The present study discovered that the stability of the substrate receptor of an E3 ligase can be modulated by CASP-8 and suggested that administration of CASP-8 inhibitors enhances the overall effectiveness of Len-based combination therapy in myeloma.

【 授权许可】

Unknown