pORF3-driven biogenesis of lipid droplets facilitates HEV infectivity.

IF 6.9 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-10-08 DOI:10.1016/j.celrep.2025.116406

Ling-Dong Xu, Fei Zhang, Can Miao, Xinyuan Yu, Yezhang Zhu, Meng-Di Zhang, Shengduo Liu, Siddharth Sridhar, Qiming Sun, Dante Neculai, Qi Zhang, Li Shen, Tingbo Liang, Cunqi Ye, Yao-Wei Huang, Pinglong Xu

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引用次数: 0

Abstract

Lipid droplets (LDs) are dynamic organelles that mediate lipid metabolism and various cellular processes. However, the interplay between hepatocyte LDs and hepatitis E remains poorly understood. Using targeted lipidomics and lipid profiling in rodent models, we reveal that hepatitis E virus (HEV) infection substantially increases hepatic LD biogenesis. Mechanistically, HEV pORF3 is a key LD biogenesis inducer and an essential factor for viral infectivity in vivo. pORF3 undergoes liquid-liquid phase-separation to form condensates that associate with LD phospholipid monolayer peripherally to upregulate cholesterol anabolic pathways, thereby promoting triacylglycerol and cholesterol ester synthesis. Consistently, genetic loss of ORF3 or pharmacologic reduction of LD biogenesis with the statin atorvastatin substantially suppressed HEV infection in vivo. These findings identify LD biogenesis as a host dependency for HEV infectivity and propose alternative strategies for HEV intervention by targeting LD-directed metabolic pathways.

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porf3驱动的脂滴生物发生促进了HEV感染。

脂滴是调节脂质代谢和各种细胞过程的动态细胞器。然而，肝细胞ld与戊型肝炎之间的相互作用仍然知之甚少。在啮齿类动物模型中使用靶向脂质组学和脂质谱分析，我们发现戊型肝炎病毒（HEV）感染显著增加肝脏LD的生物发生。从机制上讲，HEV pORF3是一种关键的LD生物发生诱导剂，是体内病毒感染的重要因子。pORF3通过液-液相分离形成凝聚物，与LD磷脂单层外周结合，上调胆固醇合成代谢途径，从而促进三酰甘油和胆固醇酯的合成。与此一致的是，ORF3基因缺失或他汀类药物阿托伐他汀降低LD生物发生的药理学水平，在体内可显著抑制HEV感染。这些发现确定了LD的生物发生是HEV感染的宿主依赖性，并提出了通过靶向LD指导的代谢途径干预HEV的替代策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.