ATGs ubiquitination is required for circumsporozoite protein to subvert host innate immunity against malaria liver stage

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.