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

文献类型： 外文期刊

作者： Liu, Xing 1 ; Liu, Tianxu 2 ; Shao, Zhen 1 ; Xiong, Xiaoyan 1 ; Qi, Shuhui 1 ; Guan, Junyong 1 ; Wang, Menghang 1 ; Tang, Yan-Dong 1 ; Feng, Zongdi 5 ; Wang, Lin 2 ; Yin, Xin 1 ;

作者机构： 1.Chinese Acad Agr Sci, Harbin Vet Res Inst, Div Livestock Infect Dis, State Key Lab Anim Dis Control & Prevent, Harbin 150069, Peoples R China

2.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Microbiol, Beijing 100191, Peoples R China

3.Peking Univ, Infect Dis Ctr, Hlth Sci Ctr, Sch Basic Med Sci, Beijing 100191, Peoples R China

4.Wageningen Univ, Dept Anim Sci, Quantitat Vet Epidemiol Grp, NL-6700 AH Wageningen, Netherlands

5.Nationwide Childrens Hosp, Res Inst, Ctr Vaccines & Immun, Columbus, OH 43205 USA

6.Ohio State Univ, Coll Med, Dept Pediat, Columbus, OH 43205 USA

关键词： hepatitis E virus; |ORF3 vesicle; exosome; quasi- enveloped virus; assembly

期刊名称：PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA （ 影响因子：9.1； 五年影响因子：10.6 ）

ISSN： 0027-8424

年卷期： 2025 年 122 卷 1 期

页码：

收录情况： SCI

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.

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