登革热和寨卡病毒感染期间STT3A介导的巨型蛋白复合体组装

STT3A-mediated mega protein complex assembly during dengue and Zika virus infection.

作者信息

Liu Tao, Hanners Natasha W, Tao Huangheng, Szabo Claudia, Xu Dao, Lin Wei, Schoggins John W, Yan Nan, Wu Jianjun

机构信息

Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

出版信息

iScience. 2025 Apr 28;28(6):112535. doi: 10.1016/j.isci.2025.112535. eCollection 2025 Jun 20.

DOI:10.1016/j.isci.2025.112535

PMID:40612902

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12225894/

Abstract

Flavivirus replication in mammalian cells requires host oligosaccharyltransferase (OST) complex, which is classically known to catalyze protein N-glycosylation. However, enzymatic activity of OST is not required for flavivirus infection, leaving the underlying mechanism puzzling. We show the STT3A sub-complex of OST, including STT3A and DC2, to be critically required for dengue virus (DENV) and Zika virus (ZIKV) infection. We find that STT3A nucleates a mega protein complex assembly during DENV infection as a scaffold through its interaction with other OST subunits, translocon proteins, and viral nonstructural proteins. The integrity of this mega protein complex is important for supporting flavivirus infection. We also identified a small-molecule compound NSC-323241 that disrupts STT3A-mediated mega protein complex assembly and potently blocks DENV and ZIKV infection. Together, our study reveals a scaffolding function of STT3A in flavivirus infection through comprehensive molecular dissection of the multi-subunit OST complex and associated host and viral proteins.

摘要

黄病毒在哺乳动物细胞中的复制需要宿主寡糖基转移酶（OST）复合体，该复合体传统上被认为可催化蛋白质N-糖基化。然而，黄病毒感染并不需要OST的酶活性，这使得其潜在机制令人费解。我们发现，OST的STT3A亚复合体，包括STT3A和DC2，对于登革热病毒（DENV）和寨卡病毒（ZIKV）感染至关重要。我们发现，在DENV感染期间，STT3A通过与其他OST亚基、转运体蛋白和病毒非结构蛋白相互作用，作为支架促成一个大型蛋白质复合体的组装。这个大型蛋白质复合体的完整性对于支持黄病毒感染很重要。我们还鉴定出一种小分子化合物NSC-323241，它可破坏STT3A介导的大型蛋白质复合体组装，并有效阻断DENV和ZIKV感染。总之，我们的研究通过对多亚基OST复合体以及相关宿主和病毒蛋白进行全面的分子剖析，揭示了STT3A在黄病毒感染中的支架功能。