HSP90 C-terminal domain inhibition promotes VDAC1 oligomerization via decreasing K274 mono-ubiquitination in Hepatocellular Carcinoma.
HSP90 C-terminal domain inhibition promotes VDAC1 oligomerization via decreasing K274 mono-ubiquitination in Hepatocellular Carcinoma.
复制标题
HSP90 C末端结构域抑制通过降低肝细胞癌中的K274单泛素化来促进VDAC1低聚。
DOI：
10.1016/j.neo.2023.100935
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发表时间：
2023-10
期刊：
影响因子：
4.8
通讯作者：
Zou, Fei
中科院分区：
文献类型：
--
作者：
Zhang, Jinxin;Liu, Lixia;Li, Yan;Huang, Yaling;Xiao, Senbo;Deng, Zihao;Zheng, Zhenming;Li, Jieyou;Liang, Manfeng;Xie, Guantai;Chen, Xiao;Deng, Yaotang;Tan, Wenchong;Su, Hairou;Wu, Guibing;Cai, Chunqing;Chen, Xuemei;Zou, Fei
关键词：
电压依赖性阴离子选择通道蛋白1(VDAC1)是线粒体外膜中含量最丰富的蛋白质，在控制肝细胞癌的进展中起着关键作用。我们以前的研究发现，胞质分子伴侣热休克蛋白90(Hsp90)与VDAC1相互作用，但Hsp90的C端和N端结构域对VDAC1寡聚体形成的影响尚不清楚。在这项研究中，我们重点研究了Hsp90的C-末端结构域对VDAC1寡聚、泛素化和VDAC1通道活性的影响。我们发现Hsp90C末端结构域抑制剂Novobiocin促进VDAC1寡聚，细胞色素c的释放，并激活线粒体的凋亡途径。原子粗粒子模拟揭示了HSP90α稳定的VDAC1单体的C-末端结构域。膜片钳电生理实验表明，Hsp90C端抑制剂Novobiocin通过促进VDAC1齐聚，增加了VDAC1的通道电导。线粒体泛素化蛋白质组学结果显示，新霉素治疗后VDAC1 K274单泛素化显著降低。VDAC1(K274R)的定点突变减弱了α与VDAC1的相互作用，增加了VDAC1的寡聚化。综上所述，我们的结果表明，抑制Hsp90 C-末端结构域通过降低VDAC1 K274的单泛素化来促进VDAC1的寡聚和VDAC1的通道电导，这为线粒体靶向治疗肝癌提供了新的视角。
Voltage-dependent anion-selective channel protein 1 (VDAC1) is the most abundant protein in the mitochondrial outer membrane and plays a crucial role in the control of hepatocellular carcinoma (HCC) progress. Our previous research found that cytosolic molecular chaperone heat shock protein 90 (Hsp90) interacted with VDAC1, but the effect of the C-terminal and N-terminal domains of Hsp90 on the formation of VDAC1 oligomers is unclear. In this study, we focused on the effect of the C-terminal domain of Hsp90 on VDAC1 oligomerization, ubiquitination, and VDAC1 channel activity. We found that Hsp90 C-terminal domain inhibitor Novobiocin promoted VDAC1 oligomerization, release of cytochrome c, and activated mitochondrial apoptosis pathway. Atomic coarse particle modeling simulation revealed C-terminal domain of Hsp90α stabilized VDAC1 monomers. The purified VDAC1 was reconstituted into a planar lipid bilayer, and electrophysiology experiments of patch clamp showed that the Hsp90 C-terminal inhibitor Novobiocin increased VDAC1 channel conductance via promoting VDAC1 oligomerization. The mitochondrial ubiquitination proteomics results showed that VDAC1 K274 mono-ubiquitination was significantly decreased upon Novobiocin treatment. Site-directed mutation of VDAC1 (K274R) weakened Hsp90α-VDAC1 interaction and increased VDAC1 oligomerization. Taken together, our results reveal that Hsp90 C-terminal domain inhibition promotes VDAC1 oligomerization and VDAC1 channel conductance by decreasing VDAC1 K274 mono- ubiquitination, which provides a new perspective for mitochondria-targeted therapy of HCC.
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影响因子：
6.7
作者：
Kurop MK;Huyen CM;Kelly JH;Blagg BSJ
通讯作者：
Blagg BSJ
影响因子：
16.6
作者：
Bridges HR;Fedor JG;Blaza JN;Di Luca A;Jussupow A;Jarman OD;Wright JJ;Agip AA;Gamiz-Hernandez AP;Roessler MM;Kaila VRI;Hirst J
通讯作者：
Hirst J
影响因子：
4.1
作者：
Geula, Shay;Ben-Hail, Danya;Shoshan-Barmatz, Varda
通讯作者：
Shoshan-Barmatz, Varda
影响因子：
--
作者：
Ben-Hail, Danya;Shoshan-Barmatz, Varda
通讯作者：
Shoshan-Barmatz, Varda
影响因子：
4.8
作者：
Ben-Hail, Danya;Begas-Shvartz, Racheli;Shoshan-Barmatz, Varda
通讯作者：
Shoshan-Barmatz, Varda