Stress responses in flavivirus-infected cells: activation of unfolded protein response and autophagy

Abstract

The Flavivirus is a genus of RNA viruses that includes multiple long known human, animal, and zoonotic pathogens such as Dengue virus, yellow fever virus, West Nile virus, or Japanese encephalitis virus, as well as other less known viruses that represent potential threats for human and animal health such as Usutu or Zika viruses. Flavivirus replication is based on endoplasmic reticulum-derived structures. Membrane remodeling and accumulation of viral factors induce endoplasmic reticulum stress that results in activation of a cellular signaling response termed unfolded protein response (UPR), which can be modulated by the viruses for their own benefit. Concomitant with the activation of the UPR, an upregulation of the autophagic pathway in cells infected with different flaviviruses has also been described. This review addresses the current knowledge of the relationship between endoplasmic reticulum stress, UPR, and autophagy in flavivirus-infected cells and the growing evidences for an involvement of these cellular pathways in the replication and pathogenesis of these viruses.

Keywords: West Nile virus; autophagy; dengue virus; endoplasmic reticulum stress; flavivirus; unfolded protein response; virus replication.

FIGURE 1

Schematic view of flavivirus connection with the ER. The alterations in the ER architecture in flavivirus-infected cells are highlighted. A representative electron micrograph of HeLa cells infected with the flavivirus WNV is shown as an example of these alterations in the ER. Note electron dense virions and vesicle packets. Micrograph courtesy of Miguel A. Martín-Acebes.

FIGURE 2

Cell signaling pathways of the UPR, autophagy connections and flaviviruses. The three arms of UPR (PERK, ATF-6, IRE-1) are shown in the figure. The viruses from the Flaviviridae family whose infection has been related to each process have been noted in the figure. See the text for details.