Palmitoylation-dependent association with Annexin II directs hepatitis E virus ORF3 sorting into vesicles and quasi-enveloped virions
Abstract
Historically considered to be nonenveloped, hepatitis E virus (HEV), an important zoonotic pathogen, has recently been discovered to egress from infected cells as quasi-enveloped virions. These quasi-enveloped virions circulating in the blood are resistant to neutralizing antibodies, thereby facilitating the stealthy spread of infection. Despite abundant evidence of the essential role of the HEV-encoded ORF3 protein in quasi-enveloped virus formation, the underlying mechanism remains unclear. Here, we demonstrate that the HEV ORF3 protein possesses an inherent capacity for self-secretion and that palmitoylation at two cysteine residues within the ORF3 N-terminal region is essential for its secretion and quasi-enveloped virus formation. We further found that only palmitoylated ORF3 proteins hijacked Annexin II for transport to the cytoskeleton and are then directed into multivesicular bodies through the nSMase-endosomal sorting complexes required for transport-III pathway for secretion. Finally, we show that infection of gerbils with HEV mutants harboring mutations at palmitoylation sites within ORF3 showed no fecal viral shedding but competent replication in the liver. Our study fills a gap in the understanding of the assembly and release of quasi-enveloped virions mediated by ORF3 and offers the potential for designing therapeutic strategies to control HEV infection.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (11)
Xing Liu
Tianxu Liu
Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center
Zhen Shao
Division of Livestock Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences
Xiaoyan Xiong
Division of Livestock Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences
Shuhui Qi
Division of Livestock Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences
Junyong Guan
Division of Livestock Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences
Menghang Wang
Division of Livestock Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences
Yan-Dong Tang
Division of Livestock Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences
Zongdi Feng
Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital
Lin Wang
Xin Yin
Faculty of Physics and CeNS