The ORF3 protein of porcine circovirus type 2 promotes secretion of IL-6 and IL-8 in porcine epithelial cells by facilitating proteasomal degradation of regulator of G protein signalling 16 through physical interaction

Abstract

Porcine circovirus type 2 (PCV2) is the main aetiological agent of postweaning multisystemic wasting syndrome. The mechanism of pathogenicity associated with PCV2 infection is still not fully understood. Nevertheless, the fact that large amounts of proinflammatory cytokines within lymphoid tissues are released during the early stage of PCV2 infection may induce chronic inflammatory responses followed by the destruction of lymphoid tissues. However, how PCV2 infection causes an excessive inflammatory response in the host immune system during the early stage of PCV2 infection has still not been elucidated. In this study, we show that direct interaction between the PCV2 ORF3 and regulator of G protein signalling 16 (RGS16) within the cytoplasm of host cells leads to ubiquitin-mediated proteasomal degradation of RGS16. Facilitated degradation of the RGS16 by PCV2 ORF3 further enhances NFkB translocation into the nucleus through the ERK1/2 signalling pathway and increased IL-6 and IL-8 mRNA transcripts. Consequently, more severe inflammatory responses and leukocyte infiltration occur around host cells. This evidence may be the first clue explaining the molecular basis of how excessive amounts of proinflammatory cytokines within lymphoid tissues are released during the early stage of PCV2 infection.

Suppressor of cytokine signaling 3 plays an important role in porcine circovirus type 2 subclinical infection by downregulating proinflammatory responses

“…PBMCs from PCV2-infected piglets with PMWS show increased IL-2, IL-4, IL-6, and IL-10 levels1011, and PK-15 cells infected with PCV2 produce IL-6, according to Choi et al 41…”

Effect of atovastatin treatment on porcine circovirus 2 infection in BALB/c mice

“…IL‐10 and proinflammatory cytokines were upregulated in PCV2‐infected pigs with porcine circovirus‐associated disease (PCVAD), which may contribute to pathogenesis . Moreover, the ORF3 protein of PCV2 promotes secretion of IL‐6 in porcine epithelial cells . PCV2‐induced cell death is enhanced in interferon gamma (IFN‐ γ )‐treated cells .…”

Interactions of porcine circovirus 2 with its hosts

“…IL-10 and proinflammatory cytokines are up-regulated in pigs with PCVD/PCVAD [48,106]. Moreover, the ORF3 protein promotes the secretion of IL-6 in porcine epithelial cells [66]. IL-2 was increased, whereas IFN-c was slightly decreased in the diseased pigs [107].…”

“…Zinc finger protein 265 (ZNF265) can interact with the PCV2 Rep protein to enhance transcription and splicing [64,65]. Direct interaction between the ORF3 protein and regulator of G protein signaling 16 (RGS16) in PK15 cells causes ubiquitinmediated proteasomal degradation of RGS16, which subsequently enhances NF-kappa B (NFjB) translocation into the nucleus through the extracellular signal-regulated kinase (ERK) 1/2 signaling pathway [65,66]. Additionally, PCV2 genomic replication requires the ubiquitin-proteasome system (UPS) machinery in a cell cycle-dependent manner [67].…”