Regulation of Ubiquitin-like with Plant Homeodomain and RING Finger Domain 1 (UHRF1) Protein Stability by Heat Shock Protein 90 Chaperone Machinery
Regulation of Ubiquitin-like with Plant Homeodomain and RING Finger Domain 1 (UHRF1) Protein Stability by Heat Shock Protein 90 Chaperone Machinery
复制标题
通过热激蛋白 90 伴侣机械调节植物同源结构域和环指结构域 1 (UHRF1) 的类泛素蛋白稳定性
DOI：
10.1074/jbc.m116.727214
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发表时间：
2016-09-16
影响因子：
4.8
通讯作者：
Wong, Jiemin
中科院分区：
文献类型：
--
作者：
Ding, Guangjin;Chen, Peilin;Wong, Jiemin
作为一种对DNA维持甲基化和细胞增殖至关重要的蛋白质，UHRF 1经常在各种人类癌症中高度表达，被认为是癌症治疗的药物靶点。在诱导UHRF 1蛋白降解的小分子的高通量筛选中，我们鉴定了HSP 90抑制剂17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）。我们提出的证据表明，UHRF 1与HSP 90伴侣复合物相互作用，是一种新的HSP 90客户蛋白。用17-AAG或17-二甲氨基乙氨基-17-脱甲氧基格尔德霉素对HSP 90的药理学抑制导致UHRF 1泛素化和蛋白酶体依赖性降解。有趣的是，这种HSP 90底物诱导的UHRF 1降解不依赖于CHIP和CUL 5，这两种先前鉴定的HSP 90客户蛋白的泛素E3连接酶。此外，这种降解既不依赖于UHRF 1的固有E3连接酶，也不依赖于参与调节UHRF 1稳定性的E3连接酶SCF-TRCP。我们还提供了证据表明，HSP 90抑制剂可能通过其诱导的UHRF 1降解部分抑制癌细胞增殖。总之，我们的研究结果确定UHRF 1作为一种新的HSP 90客户端蛋白，并阐明了UHRF 1的稳定性和功能的调节。
As a protein critical for DNA maintenance methylation and cell proliferation, UHRF1 is frequently highly expressed in various human cancers and is considered as a drug target for cancer therapy. In a high throughput screening for small molecules that induce UHRF1 protein degradation, we have identified the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). We present evidence that UHRF1 interacts with HSP90 chaperone complex and is a novel HSP90 client protein. Pharmacological inhibition of HSP90 with 17-AAG or 17-dimethylaminoethylamino-17-demethoxygeldanamycin results in UHRF1 ubiquitination and proteasome-dependent degradation. Interestingly, this HSP90 inhibitor-induced UHRF1 degradation is independent of CHIP and CUL5, two previously identified ubiquitin E3 ligases for HSP90 client proteins. In addition, this degradation is dependent neither on the intrinsic E3 ligase of UHRF1 nor on the E3 ligase SCF-TRCP that has been implicated in regulation of UHRF1 stability. We also provide evidence that HSP90 inhibitors may suppress cancer cell proliferation in part through its induced UHRF1 degradation. Taken together, our results identify UHRF1 as a novel HSP90 client protein and shed light on the regulation of UHRF1 stability and function.