ATG Ubiquitination Is Required for Circumsporozoite Protein to Subvert Host Innate Immunity Against Rodent Malaria Liver Stage.
ATG Ubiquitination Is Required for Circumsporozoite Protein to Subvert Host Innate Immunity Against Rodent Malaria Liver Stage.
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DOI：
10.3389/fimmu.2022.815936
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发表时间：
2022
影响因子：
7.3
通讯作者：
Xu W
中科院分区：
文献类型：
--
作者：
Zheng H;Lu X;Li K;Zhu F;Zhao C;Liu T;Ding Y;Fu Y;Zhang K;Zhou T;Dai J;Wu Y;Xu W
虽然寄生虫空泡（PV）中的肝期疟原虫的外红细胞形式（EEFs）遇到强大的宿主先天免疫，EEFs仍然可以存活并成功完成肝细胞的感染，其潜在的机制在很大程度上是未知的。在这里，我们表明，子孢子环子孢子蛋白（CSP）从寄生虫空泡易位到肝细胞质显着介导的抗性干扰素-γ（IFN-γ）的杀死EEFs。CSP对IFN-γ介导的EEFs杀伤作用的减弱依赖于其降低肝细胞中自噬相关基因（ATG）水平的能力。ATGs的下调是通过E3连接酶NEDD 4介导的增强泛素化而发生的，NEDD 4是一种当CSP通过其核定位信号（NLS）结构域从细胞质易位到肝细胞核时被CSP上调的酶。因此，我们揭示了CSP在破坏宿主先天免疫中未被认识到的作用，并为肝脏阶段感染的预防策略提供了新的思路。
Although exo-erythrocytic forms (EEFs) of liver stage malaria parasite in the parasitophorous vacuole (PV) are encountered with robust host innate immunity, EEFs can still survive and successfully complete the 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 mediated the resistance to the killing of 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.