S-亚硝基化甘油醛-3-磷酸脱氢酶在与Siah1结合后通过核转位引发凋亡性细胞死亡。

S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding.

作者信息

Hara Makoto R, Agrawal Nishant, Kim Sangwon F, Cascio Matthew B, Fujimuro Masahiro, Ozeki Yuji, Takahashi Masaaki, Cheah Jaime H, Tankou Stephanie K, Hester Lynda D, Ferris Christopher D, Hayward S Diane, Snyder Solomon H, Sawa Akira

机构信息

Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

出版信息

Nat Cell Biol. 2005 Jul;7(7):665-74. doi: 10.1038/ncb1268. Epub 2005 Jun 12.

DOI:10.1038/ncb1268

PMID:15951807

Abstract

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) influences cytotoxicity, translocating to the nucleus during apoptosis. Here we report a signalling pathway in which nitric oxide (NO) generation that follows apoptotic stimulation elicits S-nitrosylation of GAPDH, which triggers binding to Siah1 (an E3 ubiquitin ligase), nuclear translocation and apoptosis. S-nitrosylation of GAPDH augments its binding to Siah1, whose nuclear localization signal mediates translocation of GAPDH. GAPDH stabilizes Siah1, facilitating its degradation of nuclear proteins. Activation of macrophages by endotoxin and of neurons by glutamate elicits GAPDH-Siah1 binding, nuclear translocation and apoptosis, which are prevented by NO deletion. The NO-S-nitrosylation-GAPDH-Siah1 cascade may represent an important molecular mechanism of cytotoxicity.

摘要

甘油醛-3-磷酸脱氢酶（GAPDH）影响细胞毒性，在细胞凋亡过程中转移至细胞核。我们在此报告一种信号通路，其中凋亡刺激后产生的一氧化氮（NO）引发GAPDH的S-亚硝基化，进而触发其与Siah1（一种E3泛素连接酶）结合、核转位及细胞凋亡。GAPDH的S-亚硝基化增强了其与Siah1的结合，而Siah1的核定位信号介导了GAPDH的转位。GAPDH使Siah1稳定，促进其对核蛋白的降解。内毒素激活巨噬细胞以及谷氨酸激活神经元均引发GAPDH-Siah1结合、核转位及细胞凋亡，而NO缺失可阻止这些过程。NO-S-亚硝基化-GAPDH-Siah1级联反应可能是细胞毒性的一种重要分子机制。