摘要

The transcription factor c-Maf is extensively involved in the pathophysiology of multiple myeloma (MM), a fatal malignancy of plasma cells. In the present study, affinity chromatography and mass spectrometry were used to identify c-Maf ubiquitination-associated proteins, from which the E3 ligase HERC4 was found to interact with c-Maf and catalyzed its polyubiquitination and subsequent proteasome-mediated degradation. HERC4 mediated polyubiquitination at K85 and K297 in c-Maf, and this polyubiquitination could be prevented by the isopeptidase USP5. Further analysis on the NCI-60 cell line collection revealed that RPMI 8226, a MM-derived cell line, expressed the lowest level of HERC4. Primary bone marrow analysis revealed HERC4 expression was high in normal bone marrow, but was steadily decreased during myelomagenesis. These findings suggested HERC4 played an important role in MM progression. Moreover, ectopic HERC4 expression decreased MM proliferation in vitro, and delayed xenograft tumor growth in vivo. Therefore, modulation of c-Maf ubiquitination by targeting HERC4 may represent a new therapeutic modality for MM. 

译文

转录因子 c-Maf 广泛参与多发性骨髓瘤 (MM) 的病理生理过程，MM 是一种致命的浆细胞恶性肿瘤。在本研究中，亲和色谱和质谱用于鉴定 c-Maf 泛素化相关蛋白, 从中发现 E3 连接酶 HERC4 与 c-Maf 相互作用，并催化其多聚泛素化和随后蛋白酶体介导的降解。HERC4 介导了 c-Maf 中 K85 和 K297 的多聚泛素化，这种多聚泛素化可以被异肽酶 usp5 阻止。对 NCI-60 细胞系收集的进一步分析显示，MM 来源的细胞系 RPMI 8226 表达的 herc4 水平最低。初级骨髓分析显示 HERC4 在正常骨髓中高表达，但在骨髓再生过程中稳步下降。这些发现表明 HERC4 在 MM 进展中发挥了重要作用。此外，HERC4 的异位表达降低了体外 MM 的增殖，并延缓了体内异种移植瘤的生长。因此，通过靶向 HERC4 来调节 c-Maf 泛素化可能代表了 MM 的一种新的治疗方式。