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

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

doi:10.1016/j.isci.2025.112535

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

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

Authors

Tao Liu¹, Natasha W Hanners², Huangheng Tao¹, Claudia Szabo¹, Dao Xu¹, Wei Lin³, John W Schoggins², Nan Yan⁴, Jianjun Wu¹

Affiliations

¹ Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
² Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
³ Department of Mathematics and Statistics, Cleveland State University, Cleveland, OH 44115, USA.
⁴ Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

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.

Keywords: Biological sciences; Microbiology; Natural sciences; Virology.