ATG Ubiquitination Is Required for Circumsporozoite Protein to Subvert Host Innate Immunity Against Rodent Malaria Liver Stage

Frontiers in Immunology

Chenhao Zhao¹  Feng Zhu¹  Yan Ding¹  Kai Li¹  Kun Zhang¹  Yong Fu¹  Taoli Zhou¹  Taiping Liu¹  Jigang Dai²  Xiao Lu²  Hong Zheng²  Wenyue Xu³  Yuzhang Wu⁴ 

[1] Department of Pathogenic Biology, Army Medical University, Chongqing, China;Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China;Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China;The Institute of Immunology, Army Medical University, Chongqing, China;

关键词: Plasmodium;    malaria;    sporozoites;    exo-erythrocytic forms;    circumsporozoite protein;    IFN-γ;   

DOI  :  10.3389/fimmu.2022.815936

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown