Fortilin potentiates the peroxidase activity of Peroxiredoxin-1 and protects against alcohol-induced liver damage in mice.
Fortilin potentiates the peroxidase activity of Peroxiredoxin-1 and protects against alcohol-induced liver damage in mice.
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DOI：
10.1038/srep18701
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发表时间：
2016-01-04
影响因子：
4.6
通讯作者：
Fujise K
中科院分区：
文献类型：
--
作者：
Chattopadhyay A;Pinkaew D;Doan HQ;Jacob RB;Verma SK;Friedman H;Peterson AC;Kuyumcu-Martinez MN;McDougal OM;Fujise K
Fortilin 是一种促生存分子，通过与肿瘤抑制蛋白的序列特异性 DNA 结合域结合并阻止其转录激活 Bax，抑制 p53 诱导的细胞凋亡。有趣的是，fortilin 可以保护细胞免受 ROS 诱导的细胞死亡，与 p53 无关。然而，fortilin 保护细胞免受 ROS 诱导的细胞死亡的信号通路尚不清楚。在这里，我们报道了 fortilin 与抗氧化酶过氧化还原蛋白-1 (PRX1) 发生物理相互作用，保护其免受蛋白酶体介导的降解，并通过阻断其被丝氨酸/苏氨酸激酶 Mst1 失活的磷酸化来保持其酶活性。在整个动物水平上，fortilin 的肝脏特异性过度表达降低了肝脏中的 PRX1 磷酸化，增强了 PRX1 活性，并保护转基因动物免受酒精诱导的、ROS 介导的肝损伤。这些数据表明存在一种新的氧化应激处理途径，其中抗 p53 分子 fortilin 通过保护过氧化物酶 PRX1 免受降解和失活来增强过氧化物酶 PRX1。 Fortilin-PRX1 在肝脏中的相互作用可以在临床上进一步利用，以预防人类急性酒精性肝损伤。
Fortilin, a pro-survival molecule, inhibits p53-induced apoptosis by binding to the sequence-specific DNA-binding domain of the tumor suppressor protein and preventing it from transcriptionally activating Bax. Intriguingly, fortilin protects cells against ROS-induced cell death, independent of p53. The signaling pathway through which fortilin protects cells against ROS-induced cell death, however, is unknown. Here we report that fortilin physically interacts with the antioxidant enzyme peroxiredoxin-1 (PRX1), protects it from proteasome-mediated degradation, and keeps it enzymatically active by blocking its deactivating phosphorylation by Mst1, a serine/threonine kinase. At the whole animal level, the liver-specific overexpression of fortilin reduced PRX1 phosphorylation in the liver, enhanced PRX1 activity, and protected the transgenic animals against alcohol-induced, ROS-mediated, liver damage. These data suggest the presence of a novel oxidative-stress-handling pathway where the anti-p53 molecule fortilin augments the peroxidase PRX1 by protecting it against degradation and inactivation of the enzyme. Fortilin-PRX1 interaction in the liver could be clinically exploited further to prevent acute alcohol-induced liver damage in humans.