The Glycoprotein and Nucleocapsid Protein of Hantaviruses Manipulate Autophagy Flux to Restrain Host Innate Immune Responses

Summary: Hantavirus infection, which causes severe zoonotic diseases with high mortality in humans, has become a global public health concern. Here, we demonstrate that Hantaan virus (HTNV), the prevalent prototype of the hantavirus in Asia, can restrain innate immune responses by manipulating host autophagy flux. HTNV induces complete mitophagy at the early stage of infection but incomplete autophagy at the late stage, and these responses involve the viral glycoprotein (Gn) and nucleocapsid protein (NP), respectively. Gn translocates to mitochondria and interacts with TUFM, recruiting LC3B and promoting mitophagy. Gn-induced mitophagy inhibits type I interferon (IFN) responses by degrading MAVS. Additionally, we found that NP competes with Gn for binding to LC3B, which inhibits Gn-mediated autophagosome formation, and interacts with SNAP29, which prevents autophagosome-lysosome fusion. Thus, NP disturbs the autophagic degradation of Gn. These findings highlight how hantaviruses repurpose host autophagy and evade innate immune responses for their life cycle and pathogenesis. : Wang et al. report that the cooperative work of HTNV Gn and NP proteins manipulates host autophagy flux to restrain host innate immune responses for viral replication and propagation. Keywords: HTNV, Gn, NP, autophagy flux, mitophagy, MAVS, type I interferon responses, IFN, LC3B, SNAP29, viral replication, progeny virus production