Hunter Kasandra S, Miller André, Mentink-Kane Margaret, Davies Stephen J
Department of Microbiology and Immunology, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, MD, United States.
Schistosomiasis Resource Center, Biomedical Research Institute, Rockville, MD, United States.
Front Microbiol. 2021 Sep 1;12:726465. doi: 10.3389/fmicb.2021.726465. eCollection 2021.
On entering the mammalian host, schistosomes transition from a freshwater environment where resources are scarce, to an environment where there is an unlimited supply of glucose, their preferred energy substrate. Adult schistosome glycolytic activity consumes almost five times the parasite's dry weight in glucose per day to meet the parasite's energy demands, and the schistosome glycolytic enzymes and mechanisms for glucose uptake that sustain this metabolic activity have previously been identified. However, little is known of the parasite processes that regulate schistosome glucose metabolism. We previously described the ortholog of 5' AMP-Activated Protein Kinase (AMPK), which is a central regulator of energy metabolism in eukaryotes, and characterized the developmental regulation of its expression and activity in . Here we sought to explore the function of AMPK in schistosomes and test whether it regulates parasite glycolysis. Adult schistosomes mounted a compensatory response to chemical inhibition of AMPK α, resulting in increased AMPK α protein abundance and activity. RNAi inhibition of AMPK α expression, however, suggests that AMPK α is not required for adult schistosome viability . Larval schistosomula, on the other hand, are sensitive to chemical AMPK α inhibition, and this correlates with inactivity of the AMPK α gene in this life cycle stage that precludes a compensatory response to AMPK inhibition. While our data indicate that AMPK is not essential in adult schistosomes, our results suggest that AMPK regulates adult worm glycogen stores, influencing both glycogen utilization and synthesis. AMPK may therefore play a role in the ability of adult schistosomes to survive stressors such as transient glucose deprivation and oxidative stress. These findings suggest that AMPK warrants further investigation as a potential drug target, especially for interventions aimed at preventing establishment of a schistosome infection.
进入哺乳动物宿主后，血吸虫从资源稀缺的淡水环境过渡到葡萄糖供应无限的环境，葡萄糖是它们首选的能量底物。成年血吸虫的糖酵解活性每天消耗的葡萄糖几乎是寄生虫干重的五倍，以满足寄生虫的能量需求，维持这种代谢活动的血吸虫糖酵解酶和葡萄糖摄取机制此前已被确定。然而，对于调节血吸虫葡萄糖代谢的寄生虫过程却知之甚少。我们之前描述了5'AMP激活蛋白激酶（AMPK）的直系同源物，它是真核生物能量代谢的核心调节因子，并对其在[具体生物名称未给出]中的表达和活性的发育调控进行了表征。在这里，我们试图探索AMPK在血吸虫中的功能，并测试它是否调节寄生虫的糖酵解。成年血吸虫对AMPKα的化学抑制产生了补偿反应，导致AMPKα蛋白丰度和活性增加。然而，RNAi抑制AMPKα的表达表明，AMPKα对于成年血吸虫的生存能力并非必需。另一方面，幼虫期血吸虫对AMPKα的化学抑制敏感，这与该生命周期阶段AMPKα基因的无活性相关，从而排除了对AMPK抑制的补偿反应。虽然我们的数据表明AMPK在成年血吸虫中并非必不可少，但我们的结果表明AMPK调节成年虫体的糖原储存，影响糖原的利用和合成。因此，AMPK可能在成年血吸虫应对诸如短暂葡萄糖剥夺和氧化应激等应激源的生存能力中发挥作用。这些发现表明，AMPK作为潜在的药物靶点值得进一步研究，特别是对于旨在预防血吸虫感染的干预措施。
