Prolyl endopeptidase is a multifunctional host factor required for FMDV infection

  • Cell Mol Life Sci. 2025 Nov 19;82(1):408. doi: 10.1007/s00018-025-05941-0.
Kun Ma  #  1  2 ,  Rongzeng Hao  #  2 ,  Tianran Liu  1 ,  Yi Ru  2 ,  Tao Feng  2 ,  Xiaolan Qi  2 ,  Yuzhe Wang  1 ,  Bingzhou Lu  2 ,  Sen Wu  1 ,  Dan Li  2 ,  Ran Zhang  3 ,  Yaofeng Zhao  4 ,  Haixue Zheng  5
Affiliations
  • 1. Frontiers Science Center for Molecular Design Breeding, State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing, 100193, China.
  • 2. State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730046, China.
  • 3. Frontiers Science Center for Molecular Design Breeding, State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing, 100193, China. [email protected].
  • 4. Frontiers Science Center for Molecular Design Breeding, State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing, 100193, China. [email protected].
  • 5. State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730046, China. [email protected].
  • # Contributed equally.
PMID: 41258568 DOI: 10.1007/s00018-025-05941-0
Abstract

Foot-and-mouth disease virus (FMDV) poses a significant global threat to livestock production, underscoring the urgent need for a deeper understanding of virus-host interactions to develop effective prevention strategies. In this study, we identify prolyl endopeptidase (PREP) as a critical host factor in FMDV Infection. We demonstrate that PREP knockout (PREP-KO) significantly enhances host resistance to FMDV Infection by upregulating the expression of RIG-I and MDA5 mRNA. Specifically, PREP-KO destabilizes the PUM1 protein via proteasomal and apoptotic degradation pathways, thereby increasing RIG-I promoter activity. Additionally, PREP-KO inhibits the FMDV life cycle at the replication stage. In vivo experiments further reveal that PREP inhibition or knockout provides protection against FMDV Infection following a sublethal challenge in mice. Our findings identify PREP as a novel Antiviral target, providing valuable insights for development of Antiviral therapies and breeding of disease-resistant livestock.

Keywords
Foot-and-mouth disease virus; Innate immunity; Prolyl endopeptidase; Pumilio protein 1; Virus life cycle.
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