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Emerging evidence for poxvirus-mediated unfolded protein response: Lumpy skin disease virus maintains

Jinlong Tan1, Yinju Liu1, Fan Yang1

  • 1State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|April 4, 2023
PubMed

Insights

Lumpy skin disease virus (LSDV) infection causes endoplasmic reticulum (ER) stress, impacting viral replication. Targeting the unfolded protein response (UPR) pathways may offer new therapeutic strategies against poxviruses like LSDV and monkeypox.

Area of Science:

  • Virology
  • Cell Biology
  • Immunology

Background:

  • Poxvirus replication occurs in the cytoplasm, demanding significant protein synthesis that challenges cellular machinery.
  • The endoplasmic reticulum's (ER) role in the poxvirus life cycle, particularly in response to cellular stress, remains largely unexplored.
  • Understanding ER dynamics during viral infection is crucial for developing effective antiviral strategies.

Purpose of the Study:

  • To investigate the impact of lumpy skin disease virus (LSDV) infection on the endoplasmic reticulum (ER) and the unfolded protein response (UPR).
  • To elucidate the specific UPR signaling pathways (PERK, IRE1, ATF6) involved in LSDV replication.
  • To determine the consequences of ER stress and UPR activation on viral replication and host cell homeostasis.

Main Methods:

  • Infection of cells and animal models with LSDV to induce and monitor ER stress.
  • Analysis of unfolded protein response (UPR) activation using molecular and cellular assays.
  • Assessment of viral replication under conditions of manipulated ER stress and UPR signaling.
  • Investigation of specific signaling pathways including PERK-eIF2α, IRE1-XBP1, and ATF6.

Main Results:

  • LSDV infection induces significant ER stress and activates the UPR in both in vitro and in vivo models.
  • LSDV replication is impaired in an unbalanced ER environment, indicating a requirement for cellular homeostasis.
  • Viral replication is dependent on the PERK-eIF2α and IRE1-XBP1 signaling pathways, while the ATF6 pathway is less critical.
  • LSDV actively modulates host cell processes, including repression of global translation and ER chaperone transcription, to maintain homeostasis.

Conclusions:

  • LSDV infection disrupts cellular homeostasis by inducing ER stress and modulating the UPR.
  • The virus strategically utilizes specific UPR pathways (PERK, IRE1) for its replication while suppressing others.
  • Targeting UPR elements presents a potential therapeutic avenue for treating LSDV and related poxvirus infections, including monkeypox.
Keywords:
cell signalingendoplasmic reticulum stresslumpy skin disease viruspoxvirusunfolded protein response

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