The novel cereblon modulator CC-885 inhibits mitophagy via selective degradation of BNIP3L.
The novel cereblon modulator CC-885 inhibits mitophagy via selective degradation of BNIP3L.
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新型 cereblon 调节剂 CC-885 通过选择性降解 BNIP3L 抑制线粒体自噬
DOI：
10.1038/s41401-020-0367-9
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发表时间：
2020-09
影响因子：
8.2
通讯作者：
Tan MJ
中科院分区：
文献类型：
--
作者：
Hao BB;Li XJ;Jia XL;Wang YX;Zhai LH;Li DZ;Liu J;Zhang D;Chen YL;Xu YH;Lee SK;Xu GF;Chen XH;Dang YJ;Liu B;Tan MJ
线粒体自噬是介导整个线粒体降解的降解途径，并且该过程中的缺陷与包括癌症在内的许多疾病有关。在哺乳动物中，线粒体自噬由BNIP 3L（也称为NIX）介导，BNIP 3L是线粒体周转和程序性细胞死亡途径的双重调节剂。BNIP 3L缺乏的急性髓性白血病（AML）细胞对靶向药物更敏感。但是目前还没有BNIP 3L的小分子抑制剂。一些免疫调节药物（IMiDs）已被FDA证实可用于治疗血液系统恶性肿瘤，但其作用机制尚不明确，阻碍了BNIP 3L抑制剂在AML治疗中的应用。在这项研究中，我们进行了基于MS的定量蛋白质组学分析，以确定一种新的沙利度胺衍生物CC-885在A549细胞中的潜在新底物。总共，我们定量了5029种蛋白质，其中36种在CC-885施用后在CRBN+/+细胞中下调。生物信息学分析表明，CC-885处理后，巨噬细胞吞噬途径在阴性途径中富集。我们进一步发现，CC-885在CRBN+/+细胞中引起BNIP 3L的剂量和时间依赖性降解，但在CRBN−/−细胞中则不然。因此，我们的数据揭示了CC-885通过靶向BNIP 3L进行CRL 4CRBN E3连接酶依赖性泛素化和降解来调节线粒体自噬的新作用，这表明CC-885可以用作BNIP 3L的选择性降解剂用于进一步研究。此外，我们证明了CC-885可以增强AML细胞对靶向药物鱼藤酮的敏感性，这表明CC-885和靶向药物的组合可能是AML患者的治疗策略。
Mitophagy is a degradative pathway that mediates the degradation of the entire mitochondria, and defects in this process are implicated in many diseases including cancer. In mammals, mitophagy is mediated by BNIP3L (also known as NIX) that is a dual regulator of mitochondrial turnover and programmed cell death pathways. Acute myeloid leukemia (AML) cells with deficiency of BNIP3L are more sensitive to mitochondria-targeting drugs. But small molecular inhibitors for BNIP3L are currently not available. Some immunomodulatory drugs (IMiDs) have been proved by FDA for hematologic malignancies, however, the underlining molecular mechanisms are still elusive, which hindered the applications of BNIP3L inhibition for AML treatment. In this study we carried out MS-based quantitative proteomics analysis to identify the potential neosubstrates of a novel thalidomide derivative CC-885 in A549 cells. In total, we quantified 5029 proteins with 36 downregulated in CRBN+/+cell after CC-885 administration. Bioinformatic analysis showed that macromitophagy pathway was enriched in the negative pathway after CC-885 treatment. We further found that CC-885 caused both dose- and time-dependent degradation of BNIP3L in CRBN+/+, but not CRBN−/−cell. Thus, our data uncover a novel role of CC-885 in the regulation of mitophagy by targeting BNIP3L for CRL4CRBN E3 ligase-dependent ubiquitination and degradation, suggesting that CC-885 could be used as a selective BNIP3L degradator for the further investigation. Furthermore, we demonstrated that CC-885 could enhance AML cell sensitivity to the mitochondria-targeting drug rotenone, suggesting that combining CC-885 and mitochondria-targeting drugs may be a therapeutic strategy for AML patients.
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DOI：
10.1126/science.aab1433
发表时间：
2015-06-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Winter GE;Buckley DL;Paulk J;Roberts JM;Souza A;Dhe-Paganon S;Bradner JE
通讯作者：
Bradner JE
影响因子：
3.4
作者：
Wang, Yuexi;Yang, Feng;Gritsenko, Marina A.;Wang, Yingchun;Clauss, Therese;Liu, Tao;Shen, Yufeng;Monroe, Matthew E.;Lopez-Ferrer, Daniel;Reno, Theresa;Moore, Ronald J.;Klemke, Richard L.;Camp, David G., II;Smith, Richard D.
通讯作者：
Smith, Richard D.
影响因子：
32.4
作者：
O'Sullivan TE;Johnson LR;Kang HH;Sun JC
通讯作者：
Sun JC
DOI：
10.1073/pnas.0914013107
发表时间：
2010-05-18
影响因子：
11.1
作者：
Chen, Yun;Lewis, William;Dorn, Gerald W., II
通讯作者：
Dorn, Gerald W., II
影响因子：
158.5
作者：
Singhal, S;Mehta, J;Crowley, J
通讯作者：
Crowley, J