Porcine reproductive and respiratory syndrome virus non-structural protein 4 cleaves guanylate-binding protein 1 via its cysteine proteinase activity to antagonize GBP1 antiviral effect.

Abstract

Porcine reproductive and respiratory syndrome (PRRS) is a highly infectious disease caused by PRRS virus (PRRSV) that causes great economic losses to the swine industry worldwide. PRRSV has been recognized to modulate the host antiviral interferon (IFN) response and downstream interferon-stimulated gene expression to intercept the antiviral effect of host cells. Guanylate-binding proteins (GBPs) are IFN-inducible GTPases that exert broad antiviral activity against several DNA and RNA viruses, of which GBP1 is considered to play a pivotal role. However, the role of GBP1 in PRRSV replication remains unknown. The present study showed that overexpression of GBP1 notably inhibited PRRSV infection, while the knockdown of endogenous GBP1 promoted PRRSV infection. The K51 and R48 residues of GBP1 were essential for the suppression of PRRSV replication. Furthermore, GBP1 abrogated PRRSV replication by disrupting normal fibrous actin structures, which was indispensable for effective PRRSV replication. By using a co-immunoprecipitation assay, we found that GBP1 interacted with the non-structural protein 4 (nsp4) protein of PRRSV, and this interaction was mapped to the N-terminal globular GTPase domain of GBP1 and amino acids 1-69 of nsp4. PRRSV infection significantly downregulated GBP1 protein expression in Marc-145 cells, and nsp4, a 3C-like serine proteinase, was responsible for GBP1 cleavage, and the cleaved site was located at glutamic acid 338 of GBP1. Additionally, the anti-PRRSV activity of GBP1 was antagonized by nsp4. Taken together, these findings expand our understanding of the sophisticated interaction between PRRSV and host cells, PRRSV pathogenesis and its mechanisms of evading the host immune response.

• Authors: Hong Duan, Haoxin Dong, Shuya Wu, Jiahui Ren, Mingfang Zhang, Chuangwei Chen, Yongkun Du, Gaiping Zhang, Angke Zhang
• Journal: Veterinary research (Vet Res) Vol. 53 Issue 1 Pg. 55 (Jul 08 2022) ISSN: 1297-9716 [Electronic] England
• PMID: 35804432 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Antiviral Agents
• Interferons
• Cysteine Proteases

Topics

• Animals
• Antiviral Agents
• Cell Line
• Cysteine Proteases
• Host-Pathogen Interactions
• Interferons
• Porcine Reproductive and Respiratory Syndrome
• Porcine respiratory and reproductive syndrome virus
• Swine
• Swine Diseases
• Virus Replication