Molecular mechanisms of flavivirus membrane fusion

Abstract

Flaviviruses comprise a number of important human pathogens including yellow fever, dengue, West Nile, Japanese encephalitis and tick-borne encephalitis viruses. They are small enveloped viruses that enter cells by receptor-mediated endocytosis and release their nucleocapsid into the cytoplasm by fusing their membrane with the endosomal membrane. The fusion event is triggered by the acidic pH in the endosome and is mediated by the major envelope protein E. Based on the atomic structures of the pre- and post-fusion conformations of E, a fusion model has been proposed that includes several steps leading from the metastable assembly of E at the virion surface to membrane merger and fusion pore formation trough conversion of E into a stable trimeric post-fusion conformation. Using recombinant subviral particles of tick-borne encephalitis virus as a model, we have defined individual steps of the molecular processes underlying the flavivirus fusion mechanisms. This includes the identification of a conserved histidine as being part of the pH sensor in the fusion protein that responds to the acidic pH and thus initiates the structural transitions driving fusion.

Usutu virus: current knowledge and future perspectives

“…As reported for other flaviviruses, the mechanism of penetration into the cytoplasm must be initiated by the fusion of the viral E with the membranes of the cellular endosomes from the host cell, a process triggered by the acidic pH inside cellular endosomes. 38 The implication of cellular cofactors in membrane rearrangements induced by USUV has been analyzed by transmission electron microscopy after USUV infection, showing, as previously reported for other flaviviruses, 39 the presence of vesicle packets with electron-dense virions 40 ( Figure 3B). Lipid requirement analyses for USUV replication have confirmed fatty acid and other cellular lipids as essentials for replication, since treatment with acetyl coenzyme A carboxylase inhibitors impaired USUV multiplication.…”

Studies of the “Chain Reversal Regions” of the Avian Sarcoma/Leukosis Virus (ASLV) and Ebolavirus Fusion Proteins: Analogous Residues Are Important, and a His Residue Unique to EnvA Affects the pH Dependence of ASLV Entry

“…His residues, which are sensors for many pH-controlled conformational switches, are utilized by several viral fusion proteins as part of their fusion triggers (reviewed in references 19 and 38). Mutation of some of these His residues inhibits fusion altogether (4,5,13,38), while mutation of others alters the pH dependence of fusion (31,34,37,39). EnvA H428A is shifted ϩ0.6 pH units for fusion, which is a large pH shift compared to those recorded for His mutations in other viral fusion proteins.…”

Autographa californica Multiple Nucleopolyhedrovirus GP64 Protein: Roles of Histidine Residues in Triggering Membrane Fusion and Fusion Pore Expansion

“…In some cases, a single critical or dominant histidine residue has been proposed to serve as a functional pH sensor and trigger (12,14). In other studies, data suggest that multiple histidines (and other residues) play key roles in low-pH sensing and initiation of the conformational changes associated with triggering membrane fusion (31,39,45,49). Detailed studies of a variety of models will be required to develop a clear understanding of the variation and mechanistic complexity of low-pH sensing and the forces that initiate and propagate the conformational changes required for viral membrane fusion.…”