Emerging evidence for poxvirus‐mediated unfolded protein response: Lumpy skin disease virus maintains self‐replication by activating PERK and IRE1 signaling

Abstract

The monkeypox epidemic has attracted global attention to poxviruses. 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 member of the poxvirus family, 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 significance 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‐eIF2α and IRE1‐XBP1 signaling cascades rather than ATF6, implying that global translation and reduced XBP1 cleavage are deleterious to LSDV replication. Taken together, these findings indicate that LSDV is involved in the repression of global translational signaling, ER chaperone transcription, and ATF6 cleavage from the Golgi into the nucleus, thereby maintaining cell homeostasis; moreover, PERK and IRE1 activation contribute to LSDV replication. Our findings suggest that targeting UPR elements may be applied in response to infection from LSDV or even other poxviruses, such as monkeypox.

Lumpy Skin Disease Virus Infection Activates Autophagy and Endoplasmic Reticulum Stress-Related Cell Apoptosis in Primary Bovine Embryonic Fibroblast Cells

“…Our previous studies demonstrated that LSDV induces ER stress [ 18 ], corresponding to an ER dilatation phenotype in LSDV-infected BEF cells. Hence, apoptosis driven by the ER-related death pathway was considered to possibly play a pivotal role in the infection of BEF cells by LSDV.…”

“…However, it is still unclear how LSDV interacts with host cells, especially the target BEF cells. In a prior study, we demonstrated that LSDV infection activates all three branches of the unfolded protein response in BEF cells [ 18 ]. Among these activated signals, protein kinase RNA-like ER kinase (PERK) activation is involved in mediating CHOP expression, an important regulator of ER stress-related apoptosis [ 38 , 39 ].…”

“…The source of BEF cells refers to our previous study [ 18 ]. To well culture the BEF cells, the following procedure was performed.…”

“…LSDV infection in bovines results in the formation of characteristic skin lesions, manifested as numerous nodules throughout their bodies [ 15 , 16 , 17 ]. An initial investigation of LSDV in our previous study [ 18 ] demonstrated that a unique UPR strategy favors LSDV replication. However, the role of LSDV-induced endoplasmic reticulum (ER) stress in host cellular processes is still poorly understood.…”

A Strainer-Based Platform for the Collection and Immunolabeling of Mouse Intestinal Organoids

“…Cell research normally focuses on one or several cellular components [5,6] and, thus, cannot well describe biological processes occurring in vivo. Despite animal research being able to reproduce various disease processes [7,8], issues such as long experimental periods [9], animal mortality [10], ethics [11], and economics [12] remain problematic.…”