Department of Infection Biology, London School of Hygiene & Tropical Medicine, London, United Kingdom.
Proteomics Laboratory, The Francis Crick Institute, London, United Kingdom.
mBio. 2024 Nov 13;15(11):e0253924. doi: 10.1128/mbio.02539-24. Epub 2024 Oct 10.
We previously reported that the putative serine/threonine protein phosphatase 7 (PP7) is a high-confidence substrate of the cAMP-dependent protein kinase (PKA). Here we explore the function of PP7 in asexual blood stage parasites. We show that conditional disruption of PP7 leads to a severe growth arrest. We show that PP7 is a calcium-dependent phosphatase that interacts with calmodulin and calcium-dependent protein kinase 1 (CDPK1), consistent with a role in calcium signaling. Notably, PP7 was found to be dispensable for erythrocyte invasion, but was crucial for ring-stage development, with PP7-null parasites arresting shortly following invasion and showing no transition to ameboid forms. Phosphoproteomic analysis revealed that PP7 may regulate certain PKAc substrates. Its interaction with calmodulin and CDPK1 further emphasizes a role in calcium signaling, while its impact on early ring development and PKAc substrate phosphorylation underscores its importance in parasite development.
causes malaria and is responsible for more than 600,000 deaths each year. Although effective drugs are available to treat disease, the spread of drug-resistant parasites endangers their future efficacy. It is hoped that a better understanding of the biology of malaria parasites will help us to discover new drugs to tackle the resistance problem. Our work is focused on the cell signaling mechanisms that control the development of the parasite throughout its complex life cycle. All signal transduction pathways are ultimately regulated by reversible protein phosphorylation by protein kinase and protein phosphatase enzymes. In this study, we investigate the function of calcium-dependent protein phosphatase PP7 and show that it is essential for the development of ring-stage parasites following the invasion of human erythrocytes. Our results contribute to the understanding of the erythrocytic stages of the parasite life cycle that cause malaria pathology.
我们之前报道过假定的丝氨酸/苏氨酸蛋白磷酸酶 7（PP7）是 cAMP 依赖性蛋白激酶（PKA）的高可信度底物。在这里，我们探索了 PP7 在无性血期寄生虫中的功能。我们表明，PP7 的条件性破坏会导致严重的生长停滞。我们表明，PP7 是一种钙依赖性磷酸酶，与钙调蛋白和钙依赖性蛋白激酶 1（CDPK1）相互作用，这与钙信号传导的作用一致。值得注意的是，PP7 对于红细胞入侵是可有可无的，但对于环期发育至关重要，PP7 缺失寄生虫在入侵后不久就会停止发育，并且不会转变为阿米巴样形态。磷酸蛋白质组学分析表明，PP7 可能调节某些 PKAc 底物。它与钙调蛋白和 CDPK1 的相互作用进一步强调了其在钙信号传导中的作用，而其对早期环发育和 PKAc 底物磷酸化的影响则突出了其在寄生虫发育中的重要性。
引起疟疾，每年导致超过 60 万人死亡。尽管有有效的药物可用于治疗疾病，但抗药性寄生虫的传播危及了它们未来的疗效。人们希望更好地了解疟原虫的生物学特性将有助于我们发现新的药物来解决耐药性问题。我们的工作重点是控制寄生虫在其复杂生命周期中发育的细胞信号转导机制。所有信号转导途径最终都受到蛋白激酶和蛋白磷酸酶酶的可逆蛋白磷酸化调节。在这项研究中，我们研究了钙依赖性蛋白磷酸酶 PP7 的功能，并表明它对于人红细胞入侵后环状期寄生虫的发育是必不可少的。我们的研究结果有助于了解引起疟疾病理的寄生虫红细胞阶段。
