Composition, three-dimensional structure and formation mechanism of the foot and mouth disease virus replication complexes

Positive-sense RNA virus infections induce vesicle formation within host cells to support RNA replication. By extracting and purifying foot-and-mouth disease virus (FMDV) replication complexes and comparing host cells and replication complexes through targeted lipidomics and proteomics analyses, we found that FMDV enriches host cell proteins and polyunsaturated fatty acids in viral replication complexes (VRCs) to facilitate their formation. On the basis of these findings, we propose a model in which VRCs progress from single-membrane vesicles to multi-membrane vesicles (MMVs) during FMDV replication, a process that requires coordinated contributions of host cell proteins and organelle membranes derived from multiple organelles. Our study showed that, as infection advances, FMDV converts single-membrane vesicles (SMVs) into MMVs, which aggregate to expand the surface area of the replication platform and enhance replication efficiency. These membrane structures function in FMDV replication; the endoplasmic reticulum undergoes curling and folding to support VRC assembly. Additionally, some VRCs possess outward-facing openings that permit material exchange. These findings reveal unexpected similarities between FMDV and distantly related positive-strand RNA viruses, suggesting that shared host cellular pathways are exploited to construct membrane-bound replication factories. • Revealing the Dynamic Evolution of FMDV VRCs from SMVs to MMVs • Integrating lipidomics and proteomics analyses to decipher the origins of VRCs • Discovery that VRCs membrane structures maintain an outward-opening characteristic. • Analyzing the Mechanisms of Dynamic Remodeling of the ER Membrane. • Establishing Common Replication Strategies Between FMDV and Distant Orthomyxoviruses