Flavivirus Concentrates Host ER in Main Replication Compartments to Facilitate Replication

Flavivirus remodels the host endoplasmic reticulum (ER) to generate replication compartments (RCs) as the fundamental structures to accommodate viral replication. Here, a centralized replication mode of flavivirus is reported, i.e., flavivirus concentrates host ER in perinuclear main replication compartments (MRCs) for efficient replication. Superresolution live-cell imaging demonstrated that flavivirus MRCs formed via a series of events, including multisite ER clustering, growth and merging of ER clusters, directional movement, and convergence in the perinuclear region. The dynamic activities of viral RCs are driven by nonstructural (NS) proteins and are independent of microtubules and actin. Moreover, disrupting MRCs formation by small molecule compounds inhibited flavivirus replication. Overall, the findings reveal unprecedented insight into dynamic ER reorganization by flavivirus and identify a new inhibition strategy. Flavivirus adopts a centralized replication mode, i.e., flavivirus replicates in perinuclear main replication compartments (MRCs) derived from the endoplasmic reticulum (ER). Dynamic ZIKV MRCs formation is visualized by superresolution microscopy, including multi-site ER clustering, the growth and merging of ER clusters, and directional movement toward the nucleus and convergence in the perinuclear region.image