小脑
泛素连接酶
卡林
泊马度胺
泛素
DNA连接酶
清脆的
泛素蛋白连接酶类
蛋白酶体
生物
细胞生物学
德隆
计算生物学
来那度胺
多发性骨髓瘤
遗传学
DNA
基因
免疫学
作者
Jiye Liu,Tianyu Song,Wenyong Zhou,Lijie Xing,Wang Su,Matthew Ho,Zhen Peng,Yu‐Tzu Tai,Teru Hideshima,Kenneth C. Anderson,Yong Cang
出处
期刊:Leukemia
[Springer Nature]
日期:2018-07-19
卷期号:33 (1): 171-180
被引量:62
标识
DOI:10.1038/s41375-018-0205-y
摘要
Immunomodulatory drugs (IMiDs) including lenalidomide and pomalidomide bind cereblon (CRBN) and activate the CRL4CRBN ubiquitin ligase to trigger proteasomal degradation of the essential transcription factors IKZF1 and IKZF3 and multiple myeloma (MM) cytotoxicity. We have shown that CRBN is also targeted for degradation by SCFFbxo7 ubiquitin ligase. In the current study, we explored the mechanisms underlying sensitivity of MM cells to IMiDs using genome-wide CRISPR-Cas9 screening. We validate that CSN9 signalosome complex, a deactivator of Cullin-RING ubiquitin ligase, inhibits SCFFbxo7 E3 ligase-mediated CRBN degradation, thereby conferring sensitivity to IMiDs; conversely, loss of function of CSN9 signalosome activates SCFFbxo7 complex, thereby enhancing degradation of CRBN and conferring IMiD resistance. Finally, we show that pretreatment with either proteasome inhibitors or NEDD8 activating enzyme (NAE) inhibitors can abrogate degradation and maintain levels of CRBN, thereby enhancing sensitivity to IMiDs. These studies therefore demonstrate that CSN9 signalosome complex regulates sensitivity to IMiDs by modulating CRBN expression.
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