The Glycoprotein and Nucleocapsid Protein of Hantaviruses Manipulate Autophagy Flux to Restrain Host Innate Immune Responses
Kerong Wang,
Hongwei Ma,
He Liu,
Wei Ye,
Zhuo Li,
Linfeng Cheng,
Liang Zhang,
Yingfeng Lei,
Lixin Shen,
Fanglin Zhang
Affiliations
Kerong Wang
Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi’an, Shaanxi 710069, China
Hongwei Ma
Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
He Liu
Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Wei Ye
Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Zhuo Li
Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Linfeng Cheng
Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Liang Zhang
Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Yingfeng Lei
Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Lixin Shen
Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi’an, Shaanxi 710069, China; Corresponding author
Fanglin Zhang
Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi 710032, China; Corresponding author
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