Lys-63-specific deubiquitinase BRCC36 enhances the sensitivity of multiple myeloma cells to lenalidomide by inhibiting lysosomal degradation of cereblon
Multiple myeloma (MM) is the second most common hematologic malignancy in adults. Immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide (Len), are effective in treating MM. Len promotes the recruitment of IKZF1 and IKZF3 to cereblon (CRBN), a substrate receptor of the cullin 4-RING E3 ligase (CRL4), leading to their ubiquitination and degradation, which in turn inhibits myeloma cell proliferation. However, over time, patients with MM often develop resistance to IMiDs, resulting in disease recurrence and progression. To investigate ways to enhance IMiD sensitivity in MM, this study utilized the proximity labeling technique TurboID and quantitative proteomics to identify the Lys-63-specific deubiquitinase BRCC36 as a CRBN-interacting RZ-2994 protein. Biochemical assays revealed that BRCC36, within the BRISC complex, prevents lysosomal degradation of CRBN by cleaving K63-linked polyubiquitin chains on CRBN. Additionally, further studies showed that the small-molecule compound SHIN1, which binds to BRISC complex subunit SHMT2, can increase CRBN levels by upregulating BRCC36. The combination of SHIN1 and Len was found to enhance the sensitivity of MM cells to IMiDs. This study, therefore, lays the groundwork for exploring SHIN1 and Len combination therapy as a potential treatment strategy for MM.