Although exoerythrocytic forms (EEFs) of liver stage malaria parasite in parasitophorous vacuole (PV) encountered with robust host innate immunity, EEFs can still survive and successfully complete infection of hepatocytes, and the underlying mechanism is largely unknown. Here, we showed that sporozoite circumsporozoite protein (CSP) translocated from the parasitophorous vacuole into the hepatocyte cytoplasm significantly inhibited the killing of exo-erythrocytic forms (EEFs) by interferon-gamma (IFN-γ). Attenuation of IFN-γ-mediated killing of EEFs by CSP was dependent on its ability to reduce the levels of autophagy-related genes (ATGs) in hepatocytes. The ATGs downregulation occurred through its enhanced ubiquitination mediated by E3 ligase NEDD4, an enzyme that was upregulated by CSP when it translocated from the cytoplasm into the nucleus of hepatocytes via its nuclear localization signal (NLS) domain. Thus, we have revealed an unrecognized role of CSP in subverting host innate immunity and shed new light for a prophylaxis strategy against liver-stage infection.

中文翻译：

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环子孢子蛋白需要ATG泛素化才能破坏宿主抵抗疟疾肝阶段的先天免疫力

尽管在寄生虫液泡（PV）中肝阶段疟疾寄生虫的红细胞外形式（EEF）遇到了强大的宿主先天免疫，但EEF仍然可以存活并成功完成肝细胞的感染，其潜在机制尚不清楚。在这里，我们表明，子孢子环子孢子蛋白（CSP）从寄生虫液泡转移到肝细胞质中，显着抑制了干扰素-γ（IFN-γ）杀死外红细胞形式（EEFs）。CSP对IFN-γ介导的EEF杀伤的减弱取决于其降低肝细胞自噬相关基因（ATG）水平的能力。ATG的下调是通过E3连接酶NEDD4介导的泛素化增强而发生的，一种通过CSP通过其核定位信号（NLS）域从细胞质转移到肝细胞核中而被上调的酶。因此，我们已经揭示了CSP在颠覆宿主固有免疫力中的不可识别的作用，并为针对肝阶段感染的预防策略提供了新的思路。