Ying Zhu, Wu Yuntong, Pei Yanqun, Shang Zheng, Liu Jing, Liu Qun
National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100083, China.
Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 100083, China.
Cells. 2025 Jun 3;14(11):835. doi: 10.3390/cells14110835.
The protozoan parasite transitions between acute (tachyzoite) and chronic (bradyzoite) stages, enabling lifelong persistence in hosts. Iron depletion triggers bradyzoite differentiation, with the phosphotyrosyl phosphatase activator (PTPA) identified as a key regulator. Here, we define PTPA's role in pathogenesis. PTPA forms a ternary complex with PP2A A/C subunits, validated by reciprocal pull-down assays. Depleting PTPA impaired tachyzoite proliferation, invasion, and gliding motility, while stress-induced bradyzoites exhibited defective cyst formation and vacuolar swelling. Metabolic dysregulation included amylopectin accumulation and lipid droplet proliferation. The PP2A inhibitor LB-100 phenocopied PTPA depletion, suppressing tachyzoite growth and bradyzoite differentiation. TgPTPA emerges as a linchpin coordinating PP2A activity, metabolic flux, and lifecycle transitions. Its dual roles in acute virulence and chronic persistence, combined with LB-100's efficacy, position the PTPA-PP2A axis as a promising target for antitoxoplasmosis strategies.
这种原生动物寄生虫在急性（速殖子）和慢性（缓殖子）阶段之间转变，从而能够在宿主体内终生存活。铁缺乏会触发缓殖子分化，磷酸酪氨酸磷酸酶激活剂（PTPA）被确定为关键调节因子。在此，我们确定了PTPA在发病机制中的作用。PTPA与PP2A A/C亚基形成三元复合物，这通过相互免疫沉淀实验得到验证。敲除PTPA会损害速殖子的增殖、侵袭和滑行运动能力，而应激诱导产生的缓殖子则表现出包囊形成缺陷和液泡肿胀。代谢失调包括支链淀粉积累和脂滴增殖。PP2A抑制剂LB-100模拟了PTPA敲除的效果，抑制了速殖子生长和缓殖子分化。TgPTPA成为协调PP2A活性、代谢通量和生命周期转变的关键因素。它在急性毒力和慢性存活中的双重作用，以及LB-100的功效，使PTPA-PP2A轴成为抗弓形虫病策略的一个有前景的靶点。
