Fatty acid 2-hydroxylase facilitates rotavirus uncoating and endosomal escape

• 成果类型: Article
• 署名作者: Li, Enkai; Zang, Ruochen; Kawagishi, Takahiro; Zhang, Wei; Iyer, Kruthika; Hou, Gaopeng; Zeng, Qiru; Meganck, Rita M.; Ross, Susan R.; Wang, Xin; Su, Xiong; Ding, Siyuan
• 署名单位: Washington University (WUSTL); Shandong University; University of Osaka; Washington University (WUSTL); University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; Hainan University; Hainan University; Soochow University - China
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9384
• DOI: 10.1073/pnas.2511911122
• 发表日期: 2025-09-09
• 关键词: endoplasmic-reticulum; plasma-membrane; host factors; cell; calcium; entry; identification; replication; virus; store

摘要

Despite the clinical significance of many nonenveloped viruses, the molecular mechanisms of their internalization and membrane penetration are not well understood. Rotaviruses (RVs) are nonenveloped double- stranded RNA viruses and the leading cause of severe dehydrating diarrhea in infants and young children. We identified fatty acid 2- hydroxylase (encoded by FA2H) in the fatty acid 2- hydroxylation pathway as a proviral gene that supports RV infection. Genetic ablation of FA2H interfered with an early step in RV entry for multiple human and animal strains. Intestinal epithelial cell-specific deletion of Fa2h limited RV replication and diarrhea incidence in vivo. Using transmission electron microscopy and immunofluorescence, we found that viral particles were trapped in early and late endosomes in FA2H knockout cells, preventing their further exit into the cytosol. The defect in RV infectivity could be partially restored by treatment of cells with long- chain 2- hydroxy ceramides or a calcium channel activator that this study highlights a role of fatty acid 2- hydroxylation in RV entry into host cells and offering important insights for the development of host- directed therapies targeting fatty acid 2- hydroxylation to control microbial infections.