PDF(Pubmed)
Abstract：
Multiple myeloma (MM) is the second most common hematological tumor in adults. Immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide (Len), are effective drugs for the treatment of multiple myeloma. Len can recruit IKZF1 and IKZF3 to cereblon (CRBN), a substrate receptor of the cullin 4-RING E3 ligase (CRL4), promote their ubiquitination and degradation, and finally inhibit the proliferation of myeloma cells. However, MM patients develop resistance to IMiDs over time, leading to disease recurrence and deterioration. To explore the possible approaches that may enhance the sensitivity of IMiDs to MM, in this study, we used the proximity labeling technique TurboID and quantitative proteomics to identify Lys-63-specific deubiquitinase BRCC36 as a CRBN-interacting protein. Biochemical experiments demonstrated that BRCC36 in the BRISC complex protects CRBN from lysosomal degradation by specifically cleaving the K63-linked polyubiquitin chain on CRBN. Further studies found that a small-molecule compound SHIN1, which binds to BRISC complex subunit SHMT2, can upregulate CRBN by elevating BRCC36. The combination of SHIN1 and Len can further increase the sensitivity of MM cells to IMiDs. Therefore, this study provides the basis for the exploration of a possible strategy for the SHIN1 and Len combination treatment for MM.
摘要：
多发性骨髓瘤（MM）是成人第二常见的血液肿瘤。免疫调节药物（IMiDs），如沙利度胺和来那度胺（Len），是治疗多发性骨髓瘤的有效药物。Len可以招募IKZF1和IKZF3到cereblon（CRBN），cullin4-RINGE3连接酶（CRL4）的底物受体，促进它们的泛素化和降解，并最终抑制骨髓瘤细胞的增殖。然而,MM患者随着时间的推移会对IMiDs产生耐药性，导致疾病复发和恶化。为了探索可能增强IMID对MM敏感性的可能方法，在这项研究中，我们使用邻近标记技术TurboID和定量蛋白质组学将Lys-63特异性去泛素酶BRCC36鉴定为CRBN相互作用蛋白.生化实验表明，BRISC复合物中的BRCC36通过特异性裂解CRBN上的K63连接的聚泛素链保护CRBN免受溶酶体降解。进一步的研究发现，与BRISC复合物亚基SHMT2结合的小分子化合物SHIN1可以通过升高BRCC36来上调CRBN。SHIN1和Len的组合可以进一步增加MM细胞对IMiDs的敏感性。因此,本研究为探索SHIN1和Len联合治疗MMs的可能策略提供了依据.
