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Abstract
Porcine circovirus type 2 (PCV2) is the infectious agent of postweaning multisystemic wasting syndrome (PMWS). The recently discovered open reading frame 5 (ORF5) in PCV2 genome encodes a non-structural protein. Previous study revealed that ORF5 protein inhibits cell proliferation and may interact with host transmembrane glycoprotein NMB (GPNMB). However, whether the GPNMB affects PCV2 replication and the underlying molecular mechanisms are still unknown. In this study, the transcriptome maps of PCV2-infected and ORF5-transfected porcine alveolar macrophages 3D4/2 (PAM) cells were profiled. The GPNMB gene was down-regulated in PCV2-infected and ORF5-transfected PAMs. By using glutathione S-transferase (GST) pull-down, co-immunoprecipitation (co-IP) and confocal microscopy approaches, we convincingly showed that PCV2 ORF5 protein interacts with GPNMB. Furthermore, by utilizing lentivirus mediated overexpression or knockdown approach, we showed that the cellular GPNMB significantly inhibits PCV2 replication and ORF5 expression. Moreover, GPNMB overexpressing leads to an increased Cyclin A expression and a reduced S phase, whereas GPNMB knockdown causes a decreased Cyclin A expression and a prolonged S phase. In conclusion, we identified a novel host factor GPNMB that interacts with PCV2 ORF5 protein and restricts PCV2 replication.
Highlights
Porcine circovirus type 2 (PCV2) is the leading cause of postweaning multisystemic wasting syndrome (PMWS) which brings tremendous economic losses to swine industry (Darwich et al, 2004; Opriessnig et al, 2007)
We have revealed that PCV2 ORF5 protein down-regulate Cyclin A expression and this was confirmed in the present study (Figures 7A,B) (Lv et al, 2015)
In addition to the finding that the GPNMB interacted with PCV2 ORF5 and restricted PCV2 replication, we surprisingly find that GPNMB enhanced Cyclin A expression and triggered a less proportion of cells to enter S-phase (Figures 7,8)
Summary
Porcine circovirus type 2 (PCV2) is the leading cause of postweaning multisystemic wasting syndrome (PMWS) which brings tremendous economic losses to swine industry (Darwich et al, 2004; Opriessnig et al, 2007). PCV2 is a non-enveloped, single-stranded, closed-circular DNA virus, belonging to the genus Circovirus in the family Circoviridae with 1767 or 1768 nucleotides (Meehan et al, 1997). Eleven PCV2 open reading frames (ORFs) have been predicted with six have been well characterized (Ellis et al, 1998; Li et al, 2018). The ORF1 (nucleotides 51–995) gene encodes the Rep protein to initiate replication (Mankertz et al, 1998). The ORF2-encoded Cap protein is the only structural protein and is an immune-associated protein (Nawagitgul et al, 2000). GPNMB Restricts PCV2 and Interacts With ORF5
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