The ATF6 branch of unfolded protein response and apoptosis are activated to promote African swine fever virus infection

Galindo, I; Hernáez, B; Muñoz-Moreno, R; Cuesta-Geijo, M A; Dalmau-Mena, I; Alonso, C

The ER is an essential organelle for viral replication and maturation; in the course of productive infection, a large number of viral proteins are synthesized in infected cells, where unfolded or misfolded proteins activate the ER stress response. It is therefore not surprising that viruses have evolved various mechanisms to counteract these responses that limit or inhibit viral replication. For instance, BiP is induced in cells infected with respiratory syncytial virus, 8 hanta viruses, 9 hepatitis C virus (HCV), 10 bovine viral diarrhea virus (BVDV), 11 Japanese encephalitis virus (JEV), 12 dengue 13 and enterovirus 71. 14 The induction of PERK has also been reported in infection with herpes simplex virus, 15 cytomegalovirus (CMV) 16 and BVDV. 11 The IRE1 pathway has been shown to be activated in cells infected with JEV, dengue 17 and severe acute respiratory syndrome virus, 18 whereas the ATF6 pathway is triggered upon HCV infection 19 and both IRE1 and ATF6 arms are induced during Rotavirus infection. 20 In addition, the activation of all three pathways of the UPR has been reported in infection with West Nile virus 21 and dengue. 22 Furthermore, ASFV encodes the DP71L protein homolog to GADD34, 23 which inhibits the induction of ATF4 and its downstream target CHOP. 24, 25 However, the infection does not induce the phosphorylation of PERK or the upregulation of BiP. 24 Here, we found that ASFV induces caspases 3, 9 and 12 but not caspase 8 in infected cells, as it regulates the three arms of the UPR signaling cascade, thus inhibiting the pathways that hinder viral infection and activating those that are beneficial.