Roucou X, Giannopoulos P N, Zhang Y, Jodoin J, Goodyer C G, LeBlanc A
The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, The Sir Mortimer B Davis Jewish General Hospital, Montréal, Québec, Canada.
Cell Death Differ. 2005 Jul;12(7):783-95. doi: 10.1038/sj.cdd.4401629.
Prion protein (PrP) prevents Bcl-2-associated protein X (Bax)-mediated cell death, but the step at which PrP inhibits is not known. We first show that PrP is very specific for Bax and cannot prevent Bak (Bcl-2 antagonist killer 1)-, tBid-, staurosporine- or thapsigargin-mediated cell death. As Bax activation involves Bax conformational change, mitochondrial translocation, cytochrome c release and caspase activation, we investigated which of these events was inhibited by PrP. PrP inhibits Bax conformational change, cytochrome c release and cell death in human primary neurons and MCF-7 cells. Serum deprivation-induced Bax conformational change is more rapid in PrP-null cells. PrP does not prevent active caspase-mediated cell death. PrP does not colocalize with Bax in normal or apoptotic primary neurons and cannot prevent Bax-mediated cytochrome c release in a mitochondrial cell-free system. We conclude that PrP protects against Bax-mediated cell death by preventing the Bax proapoptotic conformational change that occurs initially in Bax activation.
朊病毒蛋白（PrP）可防止Bcl-2相关蛋白X（Bax）介导的细胞死亡，但其抑制作用发生在哪个步骤尚不清楚。我们首先表明，PrP对Bax具有高度特异性，无法防止Bak（Bcl-2拮抗剂杀手1）、tBid、星形孢菌素或毒胡萝卜素介导的细胞死亡。由于Bax激活涉及Bax构象变化、线粒体易位、细胞色素c释放和半胱天冬酶激活，我们研究了这些事件中哪些被PrP抑制。PrP在人原代神经元和MCF-7细胞中抑制Bax构象变化、细胞色素c释放和细胞死亡。在PrP缺失的细胞中，血清剥夺诱导的Bax构象变化更快。PrP不能防止活性半胱天冬酶介导的细胞死亡。在正常或凋亡的原代神经元中，PrP与Bax不共定位，并且在无细胞线粒体系统中不能防止Bax介导的细胞色素c释放。我们得出结论，PrP通过防止在Bax激活过程中最初发生的Bax促凋亡构象变化来保护细胞免受Bax介导的细胞死亡。
