Loss of PDK4 switches the hepatic NF-κB/TNF pathway from pro-survival to pro-apoptosis.
Loss of PDK4 switches the hepatic NF-κB/TNF pathway from pro-survival to pro-apoptosis.
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DOI：
10.1002/hep.29902
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Wu J;Zhao Y;Park YK;Lee JY;Gao L;Zhao J;Wang L
已经确定NF-κB成员通过上调抗凋亡基因促进存活，并且NF-κB的遗传和药理学抑制是TNF诱导的肝细胞凋亡所必需的。在这项研究中，我们证明了这种促生存途径在丙酮酸脱氢酶激酶4（PDK 4）缺乏的条件下被切换到促凋亡。PDK 4缺乏引发肝细胞凋亡伴随着异常线粒体数量的增加、ROS产生、持续的JNK活化和GSH减少。有趣的是，PDK 4通过直接的蛋白质-蛋白质相互作用将p65保留在细胞质中。PDK 4-p65结合的破坏促进了p65核转位。这反过来又促进了p65与TNF启动子的结合以激活TNF-TNFR 1凋亡途径。Pdk 4 −/−肝脏对Jo 2和GalN/LPS介导的凋亡损伤敏感，这可以通过抑制p65或TNFR 1来防止。TNF的促存活活性发生变化，由于促存活NF-κB靶点的活化受损，其在Pdk 4 −/−肝细胞中转变为促凋亡活性。结论：PDK 4在TNF/NF-κ B介导的肝细胞凋亡中起重要作用。
It has been established that NF-κB members promote survival by upregulating anti-apoptotic genes and that genetic and pharmacological inhibition of NF-κB is required for TNF-induced hepatocyte apoptosis. In this study, we demonstrate that this pro-survival pathway is switched to pro-apoptosis under pyruvate dehydrogenase kinase 4 (PDK4)-deficient conditions. PDK4-deficiency triggered hepatic apoptosis concomitantly with increased numbers of aberrant mitochondria, ROS production, sustained JNK activation, and reduction of GSH. Interestingly, PDK4 retained p65 in cytoplasm via a direct protein-protein interaction. Disruption of PDK4-p65 association promoted p65 nuclear translocation. This in turn facilitated p65 binding to the TNF promoter to activate TNF-TNFR1 apoptotic pathway. Pdk4−/− livers were sensitized to Jo2 and GalN/LPS-mediated apoptotic injury which was prevented by the inhibition of p65 or TNFR1. The pro-survival activity of TNF was shifted, which was switched to a pro-apoptotic activity in Pdk4−/− hepatocytes as a result of impaired activation of pro-survival NF-κB targets. Conclusion: PDK4 is indispensible to dictate the fate of TNF/NF-κB-mediated hepatocyte apoptosis.
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DOI：
10.1002/hep.29654
发表时间：
2018-05
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Liu C;Yang Z;Wu J;Zhang L;Lee S;Shin DJ;Tran M;Wang L
通讯作者：
Wang L
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影响因子：
30.8
作者：
Panizzi JR;Becker-Heck A;Castleman VH;Al-Mutairi DA;Liu Y;Loges NT;Pathak N;Austin-Tse C;Sheridan E;Schmidts M;Olbrich H;Werner C;Häffner K;Hellman N;Chodhari R;Gupta A;Kramer-Zucker A;Olale F;Burdine RD;Schier AF;O'Callaghan C;Chung EM;Reinhardt R;Mitchison HM;King SM;Omran H;Drummond IA
通讯作者：
Drummond IA
PDK4 蛋白通过激活 cAMP 反应元件结合蛋白 (CREB)-富含脑的 Ras 同源物 (RHEB)-mTORC1 信号级联促进肿瘤发生
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
13.5
作者：
Nagai, H;Matsumaru, K;Kaplowitz, N
通讯作者：
Kaplowitz, N
影响因子：
4.8
作者：
Chambers, Jeremy W.;LoGrasso, Philip V.
通讯作者：
LoGrasso, Philip V.