Palmitoylation- dependent association with Annexin II directs hepatitis E virus ORF3 sorting into vesicles and quasi- enveloped virions

• 成果类型: Article
• 署名作者: Liu, Xing; Liu, Tianxu; Shao, Zhen; Xiong, Xiaoyan; Qi, Shuhui; Guan, Junyong; Wang, Menghang; Tang, Yan-Dong; Feng, Zongdi; Wang, Lin; Yin, Xin
• 署名单位: Chinese Academy of Agricultural Sciences; Harbin Veterinary Research Institute, CAAS; Peking University; Peking University; Wageningen University & Research; University System of Ohio; Ohio State University; Nationwide Childrens Hospital; Research Institute at Nationwide Children's Hospital; Center for Vaccines & Immunity; University System of Ohio; Ohio State University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12744
• DOI: 10.1073/pnas.2418751122
• 发表日期: 2025-01-07
• 关键词: protein; release; TRAFFICKING; mechanisms; forms; entry; LIFE; a2

摘要

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.