TAX1BP1 contributes to deoxypodophyllotoxin-induced glioma cell parthanatos via inducing nuclear translocation of AIF by activation of mitochondrial respiratory chain complex I.
TAX1BP1 contributes to deoxypodophyllotoxin-induced glioma cell parthanatos via inducing nuclear translocation of AIF by activation of mitochondrial respiratory chain complex I.
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DOI：
10.1038/s41401-023-01091-w
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发表时间：
2023-09
影响因子：
8.2
通讯作者：
Ge, Peng-fei
中科院分区：
文献类型：
--
作者：
Wang, Xuan-zhong;Liang, Shi-peng;Chen, Xi;Wang, Zhen-chuan;Li, Chen;Feng, Chun-sheng;Lu, Shan;He, Chuan;Wang, Yu-bo;Chi, Guang-fan;Ge, Peng-fei
关键词：
Parthanatos是一种由过度激活的聚（ADP-核糖）聚合酶1（PARP 1）启动的程序性细胞死亡。凋亡诱导因子（AIF）的核转位是Parthanatos的一个显著特征。但目前尚不清楚激活的核PARP 1如何诱导线粒体AIF易位到核中。有证据表明，脱氧鬼臼毒素（DPT）通过诱导过量的ROS诱导胶质瘤细胞死亡。本研究探讨了DPT诱导胶质瘤细胞凋亡过程中PARP 1激活诱导AIF核转位的下游信号。我们发现，DPT（450 nM）处理诱导PARP 1过度激活和Tax 1结合蛋白1（TAX 1BP 1）分布到人U87，U251和U118胶质瘤细胞的线粒体。PARP 1活化通过消耗烟酰胺腺嘌呤二核苷酸（NAD+）促进TAX 1BP 1分布到线粒体。用siRNA敲低TAX 1BP 1不仅可以抑制TAX 1BP 1在线粒体中的积累，而且可以减轻AIF的核转位和胶质瘤细胞的死亡。我们证明TAX 1BP 1不仅通过上调ND 1、ND 2、NDUFS 2和NDUFS 4的表达，而且还通过促进它们组装成呼吸链复合物I来增强呼吸链复合物I的活性。呼吸复合物I的激活产生更多的超氧化物，导致线粒体去极化和AIF的核转位，而线粒体超氧化物歧化酶的增加通过诱导ROS依赖的DNA双链断裂而增强PARP 1的激活。在荷人U87肿瘤异种移植瘤小鼠中，DPT（10 mg· kg-1 ·d-1，i. p.，8天）显著抑制肿瘤生长，伴随着肿瘤组织中NAD+耗竭、TAX 1BP 1分布到线粒体、AIF分布到细胞核以及DNA DSB和PARP 1活化。综上所述，这些数据表明TAX 1BP 1作为激活的PARP 1的下游信号，通过激活线粒体呼吸链复合物I触发AIF的核转位。
Parthanatos is a type of programmed cell death initiated by over-activated poly (ADP-ribose) polymerase 1 (PARP1). Nuclear translocation of apoptosis inducing factor (AIF) is a prominent feature of parthanatos. But it remains unclear how activated nuclear PARP1 induces mitochondrial AIF translocation into nuclei. Evidence has shown that deoxypodophyllotoxin (DPT) induces parthanatos in glioma cells via induction of excessive ROS. In this study we explored the downstream signal of activated PARP1 to induce nuclear translocation of AIF in DPT-triggered glioma cell parthanatos. We showed that treatment with DPT (450 nM) induced PARP1 over-activation and Tax1 binding protein 1 (TAX1BP1) distribution to mitochondria in human U87, U251 and U118 glioma cells. PARP1 activation promoted TAX1BP1 distribution to mitochondria by depleting nicotinamide adenine dinucleotide (NAD+). Knockdown of TAX1BP1 with siRNA not only inhibited TAX1BP1 accumulation in mitochondria, but also alleviated nuclear translocation of AIF and glioma cell death. We demonstrated that TAX1BP1 enhanced the activity of respiratory chain complex I not only by upregulating the expression of ND1, ND2, NDUFS2 and NDUFS4, but also promoting their assemblies into complex I. The activated respiratory complex I generated more superoxide to cause mitochondrial depolarization and nuclear translocation of AIF, while the increased mitochondrial superoxide reversely reinforced PARP1 activation by inducing ROS-dependent DNA double strand breaks. In mice bearing human U87 tumor xenograft, administration of DPT (10 mg· kg−1 ·d−1, i.p., for 8 days) markedly inhibited the tumor growth accompanied by NAD+ depletion, TAX1BP1 distribution to mitochondria, AIF distribution to nuclei as well as DNA DSBs and PARP1 activation in tumor tissues. Taken together, these data suggest that TAX1BP1 acts as a downstream signal of activated PARP1 to trigger nuclear translocation of AIF by activation of mitochondrial respiratory chain complex I.
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DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
影响因子：
9.7
作者：
Huang, Qi;Chen, Zhigang;Huang, Jian
通讯作者：
Huang, Jian
影响因子：
2.8
作者：
Nanjaiah, Hemalatha;Vallikannan, Baskaran
通讯作者：
Vallikannan, Baskaran
影响因子：
11.2
作者：
FLOYD, RA;CARNEY, JM
通讯作者：
CARNEY, JM
影响因子：
6.6
作者：
Lahiri T;Brambilla L;Andrade J;Askenazi M;Ueberheide B;Levy DE
通讯作者：
Levy DE