Flavivirus replication complex assembly revealed by DNAJC14 functional mapping. Academic Article uri icon

Overview

abstract

  • DNAJC14 is an Hsp40 family member that broadly modulates flavivirus replication. The mechanism by which DNAJC14 stoichiometrically participates in flavivirus replication complex (RC) formation is unknown; both reduced and elevated levels result in replication inhibition. Using yellow fever virus (YFV), we demonstrate that DNAJC14 redistributes and clusters with YFV nonstructural proteins via a transmembrane domain and a newly identified membrane-binding domain (MBD), which both mediate targeting to detergent-resistant membranes. Furthermore, the RC and DNAJC14 reside as part of a protein interaction network that remains after 1% Triton solubilization. Mutagenesis studies demonstrate that entry into this protein interaction network requires the DNAJC14 C-terminal self-interaction domain. Fusion of the DNAJC14 MBD and self-interaction domain with another Hsp40 family protein is sufficient to confer YFV-inhibitory activity. Our findings support a novel model of DNAJC14 action that includes specific membrane targeting of both DNAJC14 and YFV replication proteins, the formation of protein interactions, and a microdomain-specific chaperone event leading to RC formation. This process alters the properties of the RC membrane and results in the formation of a protein scaffold that maintains the RC.

publication date

  • August 22, 2012

Research

keywords

  • Fetal Proteins
  • Host-Pathogen Interactions
  • Molecular Chaperones
  • Virus Replication
  • Yellow fever virus

Identity

PubMed Central ID

  • PMC3486285

Scopus Document Identifier

  • 84869077795

Digital Object Identifier (DOI)

  • 10.1371/journal.ppat.1001255

PubMed ID

  • 22915803

Additional Document Info

volume

  • 86

issue

  • 21