Celgene Corporation, San Diego, United States.
Elife. 2018 Sep 20;7:e40958. doi: 10.7554/eLife.40958.
The cereblon modulating agents (CMs) including lenalidomide, pomalidomide and CC-220 repurpose the Cul4-RBX1-DDB1-CRBN (CRL4) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the K48-linked polyubiquitination of CRL4 neomorphic substrates via a sequential ubiquitination mechanism. Blockade of UBE2G1 diminishes the ubiquitination and degradation of neomorphic substrates, and consequent antitumor activities elicited by all tested CMs. For example, UBE2G1 inactivation significantly attenuated the degradation of myeloma survival factors IKZF1 and IKZF3 induced by lenalidomide and pomalidomide, hence conferring drug resistance. UBE2G1-deficient myeloma cells, however, remained sensitive to a more potent IKZF1/3 degrader CC-220. Collectively, it will be of fundamental interest to explore if loss of UBE2G1 activity is linked to clinical resistance to drugs that hijack the CRL4 to eliminate disease-driving proteins.
cereblon 调节因子（CMs）包括来那度胺、泊马度胺和 CC-220，它们重新利用 Cul4-RBX1-DDB1-CRBN（CRL4）E3 泛素连接酶复合物，通过与 E2 泛素连接酶协同作用，对特定的新生底物进行多泛素化，从而诱导其降解，到目前为止，这些新生底物仍然难以捉摸。在这里，我们表明泛素连接酶 UBE2G1 和 UBE2D3 通过连续的泛素化机制协同促进 CRL4 新生底物的 K48 连接多泛素化。UBE2G1 的阻断会减少新生底物的泛素化和降解，以及所有测试的 CMs 引发的抗肿瘤活性。例如，UBE2G1 的失活显著减弱了来那度胺和泊马度胺诱导的骨髓瘤生存因子 IKZF1 和 IKZF3 的降解，从而产生耐药性。然而，缺乏 UBE2G1 的骨髓瘤细胞仍然对更有效的 IKZF1/3 降解剂 CC-220 敏感。总的来说，如果 UBE2G1 活性的丧失与劫持 CRL4 消除疾病驱动蛋白的药物的临床耐药性有关，那么探索这一点将具有重要意义。
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