Joy Shiny, Thirunavukkarasu Lavanya, Agrawal Palak, Singh Archana, Sagar B K Chandrasekhar, Manjithaya Ravi, Surolia Namita
1Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, 560064 India.
2CSIR-Institue of Genomics and Integrative Biology, Room 223, Sukhdev Vihar, Mathura Road, New Delhi, 110025 India.
Cell Death Discov. 2018 Oct 3;4:43. doi: 10.1038/s41420-018-0107-9. eCollection 2018.
The precise role of autophagy in remains largely unknown. Although a limited number of autophagy genes have been identified in this apicomplexan, only Atg8 has been characterized to a certain extent. On the basis of the expression levels of Atg8 and the putative Atg5, we report that the basal autophagy in this parasite is quite robust and mediates not only the intraerythrocytic development but also fresh invasion of red blood cells (RBCs) in the subsequent cycles. We demonstrate that the basal autophagy responds to both inducers and inhibitors of autophagy. In addition, the parasite survival upon starvation is temporally governed by the autophagy status. Brief periods of starvation, which induces autophagy, help survival while prolonged starvation decreases autophagy leading to stalled parasite growth and reduced invasion. Thus, starvation-induced autophagy is context dependent. Importantly, we report characterization of another autophagy marker in this parasite, the putative Atg5 (3D7_1430400). 5 is expressed in all the intraerythrocytic stages and partially colocalizes with ER, mitochondria, apicoplast and Atg8. It is also present on the double membrane bound vesicles. Altogether, these studies pave way for the detailed dissection of autophagy machinery and insights into molecular and functional characterization of its players for developing new therapeutics as antimalarials.
自噬在疟原虫中的精确作用在很大程度上仍不清楚。尽管在这种顶复门原虫中已鉴定出数量有限的自噬基因,但只有Atg8在一定程度上得到了表征。基于Atg8和假定的Atg5的表达水平,我们报告称该寄生虫中的基础自噬相当活跃,不仅介导红细胞内发育,还介导后续周期中红细胞(RBC)的新入侵。我们证明基础自噬对自噬诱导剂和抑制剂均有反应。此外,寄生虫在饥饿状态下的存活受自噬状态的时间调控。短暂的饥饿诱导自噬,有助于存活,而长时间饥饿会降低自噬,导致寄生虫生长停滞和入侵减少。因此,饥饿诱导的自噬取决于具体情况。重要的是,我们报告了该寄生虫中另一种自噬标记物,即假定的Atg5(3D7_1430400)的表征。Atg5在所有红细胞内阶段均有表达,并与内质网、线粒体、顶质体和Atg8部分共定位。它也存在于双膜结合小泡上。总之,这些研究为详细剖析疟原虫自噬机制以及深入了解其参与者的分子和功能特征以开发新型抗疟治疗药物铺平了道路。