Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
Cell Microbiol. 2012 Apr;14(4):589-607. doi: 10.1111/j.1462-5822.2011.01745.x. Epub 2012 Feb 8.
Nutrient sensing and the capacity to respond to starvation is tightly regulated as a means of cell survival. Among the features of the starvation response are induction of both translational repression and autophagy. Despite the fact that intracellular parasite like Toxoplasma gondii within a host cell predicted to be nutrient rich, they encode genes involved in both translational repression and autophagy. We therefore examined the consequence of starvation, a classic trigger of autophagy, on intracellular parasites. As expected, starvation results in the activation of the translational repression system as evidenced by elevation of phosphorylated TgIF2α (TgIF2α-P). Surprisingly, we also observe a rapid and selective fragmentation of the single parasite mitochondrion that leads irreversibly to parasite death. This profound effect was dependent primarily on the limitation of amino acids and involved signalling by the parasite TOR homologue. Notably, the effective blockade of mitochondrial fragmentation by the autophagy inhibitor 3-methyl adenine (3-MA) suggests an autophagic mechanism. In the absence of a documented apoptotic cascade in T. gondii, the data suggest that autophagy is the primary mechanism of programmed cell death in T. gondii and potentially other related parasites.
营养感应和对饥饿做出反应的能力是作为一种细胞存活的手段受到严格调控的。饥饿反应的特征包括翻译抑制和自噬的诱导。尽管像刚地弓形虫这样的细胞内寄生虫在富含营养的宿主细胞中被预测为，它们编码涉及翻译抑制和自噬的基因。因此，我们研究了饥饿（自噬的经典触发因素）对细胞内寄生虫的后果。正如预期的那样，饥饿导致翻译抑制系统的激活，这表现为磷酸化 TgIF2α（TgIF2α-P）的升高。令人惊讶的是，我们还观察到寄生虫的单个线粒体迅速而选择性地碎片化，这导致寄生虫死亡不可逆转。这种深远的影响主要依赖于氨基酸的限制，并涉及寄生虫 TOR 同源物的信号转导。值得注意的是，自噬抑制剂 3-甲基腺嘌呤（3-MA）对线粒体碎片化的有效阻断表明存在自噬机制。在刚地弓形虫中没有记录到凋亡级联的情况下，数据表明自噬是刚地弓形虫和其他相关寄生虫程序性细胞死亡的主要机制。
