RIPK3 Promotes Hantaviral Replication by Restricting JAK-STAT Signaling but not Triggering Necroptosis.

Abstract

Hantaan virus (HTNV) is a rodent-borne virus that can cause hemorrhagic fever with renal syndrome (HFRS) with a case fatality rate of 15% and is listed as a re-emerging infectious disease (REID) in China. At present, no specific therapeutic strategies against HTNV are available. Interferon (IFN) is a crucial antiviral molecular which can trigger interferon-stimulated genes (ISGs) expression through the Janus kinase-signal transducer and activator of transcription 1 (JAK-STAT) pathway. Large quantities of IFN produced at the late stage of HTNV infection could not effectively restrain viral replication, the mechanism of which is still unclear. Here, we identified the receptor-interacting protein kinase 3 (RIPK3), a critical molecular to mediate necroptosis, could facilitate HTNV infection by blocking JAK/STAT signaling. HTNV infection promoted the total expression level of RIPK3, but not the phosphorylation of RIPK3, thus not leading to cell death. RIPK3 ablation could restrain HTNV replication by enhancing the expression of multiple ISGs, during which the type I IFN generation did not strengthened. Exogenously expressing RIPK3 might hinder the host anti-hantaviral responses. RIPK3−/− mice also maintained a robust ability to clear HTNV promptly with enhanced innate immune responses. Mechanistically, RIPK3 restricted STAT1 activation by bonding to STAT1 and blocking its phosphorylation sites, hence interfering with host IFN responses. Overall, these observations demonstrated a noncanonical function of RIPK3 during viral infection, and shed light on the novel evasion strategy of host innate immunity by HTNV.