S-Nitrosylation of Mixed Lineage Kinase 3 Contributes to Its Activation after Cerebral Ischemia

被引:49
作者
Hu, Shu-Qun [1 ,2 ]
Ye, Jun-Song [1 ,2 ]
Zong, Yan-Yan [1 ,2 ]
Sun, Chang-Cheng [1 ,2 ]
Liu, Dong-Hai [1 ,2 ]
Wu, Yong-Ping [3 ]
Song, Tao [4 ]
Zhang, Guang-Yi [1 ,2 ]
机构
[1] Xuzhou Med Coll, Jiangsu Key Lab Brain Dis Bioinformat, Xuzhou 221002, Jiangsu, Peoples R China
[2] Xuzhou Med Coll, Res Ctr Biochem & Mol Biol, Xuzhou 221002, Jiangsu, Peoples R China
[3] Xuzhou Med Coll, Jiangsu Key Lab Anesthesiol, Xuzhou 221002, Jiangsu, Peoples R China
[4] China Med Univ, Affiliated Hosp 1, Dept Anesthesiol, Shenyang 110001, Peoples R China
基金
中国国家自然科学基金;
关键词
NEURONAL NITRIC-OXIDE; RAT HIPPOCAMPUS; PROTEIN-KINASE; TUMOR-SUPPRESSOR; APOPTOSIS; MECHANISM; SYNTHASE; RECEPTOR; PATHWAY; INJURY;
D O I
10.1074/jbc.M111.227124
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Previous studies in our laboratory have shown that mixed lineage kinase 3 (MLK3) can be activated following global ischemia. In addition, other laboratories have reported that the activation of MLK3 may be linked to the accumulation of free radicals. However, the mechanism of MLK3 activation remains incompletely understood. We report here that MLK3, overexpressed in HEK293 cells, is S-nitrosylated (forming SNO-MLK3) via a reaction with S-nitrosoglutathione, an exogenous nitric oxide (NO) donor, at one critical cysteine residue (Cys-688). We further show that the S-nitrosylation of MLK3 contributes to its dimerization and activation. We also investigated whether the activation of MLK3 is associated with S-nitrosylation following rat brain is chemia/reperfusion. Our results show that the administration of 7-nitroindazole, an inhibitor of neuronal NO synthase (nNOS), or nNOS antisense oligodeoxy-nucleotides diminished the S-nitrosylation of MLK3 and inhibited its activation induced by cerebral ischemia/reperfusion. In contrast, 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (an inhibitor of inducible NO synthase) or nNOS missense oligode-oxynucleotides did not affect the S-nitrosylation of MLK3. In addition, treatment with sodium nitroprusside (an exogenous NO donor) and S-nitrosoglutathione or MK801, an antagonist of the N-methyl-D-aspartate receptor, also diminished the S-nitrosylation and activation of MLK3 induced by cerebral ischemia/reperfusion. The activation of MLK3 facilitated its downstream protein kinase kinase 4/7 (MKK4/7)-JNK signaling module and both nuclear and non-nuclear apoptosis pathways. These data suggest that the activation of MLK3 during the early stages of ischemia/reperfusion is modulated by S-nitrosylation and provides a potential new approach for stroke therapy whereby the post-translational modification machinery is targeted.
引用
收藏
页码:2364 / 2377
页数:14
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