Emerging Evidence for Poxvirus-Mediated Unfolded Protein Response: Lumpy Skin Disease Virus Maintains Self-replication by Activating PERK and IRE1

Abstract

The cytoplasmic replication of poxviruses requires extensive protein synthesis, challenging the capacity of the endoplasmic reticulum (ER). However, the role of the ER in the life cycle of poxviruses is unclear. In this study, we demonstrate that infection with the lumpy skin disease virus (LSDV), a poxvirus, causes ER stress in vivo and in vitro, further facilitating the activation of the unfolded protein response (UPR). Although UPR activation aids in the restoration of the cellular environment, its significance in the LSDV life cycle remains unclear. Furthermore, the role of ER imbalance for viral replication is also unknown. We show that LSDV replication is hampered by an unbalanced ER environment. In addition, we verify that the LSDV replication depends on the activation of PERK-eIF2 and IRE1-XBP1 signaling cascades rather than ATF6, implying that global translation and XBP1 cleavage are deleterious to LSDV replication. Our findings suggest that LSDV engages all UPR signaling sensors, and that activation of PERK and IRE1 sensors is indispensable to maintaining its own replication. IMPORTANCEAlthough numerous viruses cause ER stress and employ endogenous UPR components to control viral growth, there is no such evidence for poxviruses. Recent real-world epidemics of poxviruses such as monkeypox and LSDV indicated a lack of available coping strategies. Our findings show that LSDV encoding up to 156 open reading frames (ORFs) causes pressure to the stabilization of ER, triggers ER stress, and further promotes the activation of all three UPR signaling pathways. However, inhibiting PERK-eIF2 and IRE1-XBP1 was not conducive for LSDV replication. Since LSDV efficiently utilizes UPR components to assist its own replication, signal-blocking agents of PERK and IRE1 may be useful in the treatment of LSDV. More evidence for the efficacy of such therapy for LSDV, even monkeypox, could come from a clearer characterization of the ER stress-mediated viral replication process.