Host cytoskeletal vimentin serves as a structural organizer and an RNA-binding protein regulator to facilitate Zika viral replication

Abstract

Emerging microbe infections, such as Zika virus (ZIKV), pose an increasing threat to human health. Investigations on ZIKV replication have revealed the construction of replication complexes (RCs), but the role of cytoskeleton in this process is largely unknown. Here, we investigated the function of cytoskeletal intermediate filament protein vimentin in the life cycle of ZIKV infection. Using advanced imaging techniques, we uncovered that vimentin filaments undergo drastic reorganization upon viral protein synthesis to form a perinuclear cage-like structure that embraces and concentrates RCs. Genetic removal of vimentin markedly disrupted the integrity of RCs and resulted in fragmented subcellular dispersion of viral proteins. This led to reduced viral genome replication, viral protein production, and release of infectious virions, without interrupting viral binding and entry. Furthermore, mass spectrometry and RNA-sequencing screens identified interactions and interplay between vimentin and hundreds of endoplasmic reticulum (ER)-resident RNA-binding proteins. Among them, the cytoplasmic-region of ribosome receptor binding protein 1, an ER transmembrane protein that directly binds viral RNA, interacted with and was regulated by vimentin, resulting in modulation of ZIKV replication. Together, the data in our work reveal a dual role for vimentin as a structural element for RC integrity and as an RNA-binding-regulating hub during ZIKV infection, thus unveiling a layer of interplay between Zika virus and host cell.

Three-Dimensional Remodeling of SARS-CoV2-Infected Cells Revealed by Cryogenic Soft X-ray Tomography

“…34 Cortese et al reported similar vimentin cages in Zika virus infected cells, 35 and this structure has been proposed as a structural organizer that facilitates viral replication, at least for Zika and influenza viruses. 36,37 While the precise functional relevance of this structure remains unclear in SARS-CoV-2 infection, vimentin filaments have been proposed as physical barriers that limit intracellular vesicular trafficking, which may benefit the concentration of viral components in specific cytoplasmic locations to contribute to coordinating viral RNA replication and virion assembly. Vimentin cages may also be observed as essential components of cellular structures devoted to protein quality control, originally designated as "aggresomes" (reviewed in ref 38).…”

Mechanisms of Zika astrocyte infection and neuronal toxicity

“…Overall, ZIKV is a member of Flaviviridae and produces both infectious and noninfectious virions. Subviral particles are common during Flavivirus infection and result in uptake, but not viral production, of new virions in host cells [ 61 ], [ 62 ], [ 63 ], [ 64 ], [ 65 ], [ 66 ]. To determine the ZIKV infectivity of human astrocytes at different fetal developmental stages were inoculated with ZIKV strain PA 259,459, an Asian lineage strain isolated from an infected human, Panama in 2015.…”

Nucleocapsid condensation drives Ebola viral factory maturation and dispersion

“…This indicates the importance of vimentin for VF growth and is an initial proof-of-concept that targeting of cellular structures interacting with virus-induced biomolecular condensate may provide a viable antiviral strategy in drug development. Importantly, for Dengue virus and Zika virus vimentin was found to play a structural role in maintaining the integrity of the viral replication organelles [35, 36], raising the possibility that such a strategy might be viable against a broader spectrum of viruses.…”