The novel ORFV protein ORFV113 activates LPA-p38 signaling

Viruses have evolved mechanisms to subvert critical cellular signaling pathways that regulate a wide range of cellular functions, including cell differentiation, proliferation and chemotaxis, and innate immune responses. Here, we describe a novel ORFV protein, ORFV113, that interacts with the G protein-coupled receptor Lysophosphatidic acid receptor 1 (LPA(1)). Consistent with its interaction with LPA(1), ORFV113 enhances p38 kinase phosphorylation in ORFV infected cells in vitro and in vivo, and in cells transiently expressing ORFV113 or treated with soluble ORFV113. Infection of cells with virus lacking ORFV113 (OV-IA82 Delta 113) significantly decreased p38 phosphorylation and viral plaque size. Infection of cells with ORFV in the presence of a p38 kinase inhibitor markedly diminished ORFV replication, highlighting importance of p38 signaling during ORFV infection. ORFV113 enhancement of p38 activation was prevented in cells in which LPA(1) expression was knocked down and in cells treated with LPA(1) inhibitor. Infection of sheep with OV-IA82 Delta 113 led to a strikingly attenuated disease phenotype, indicating that ORFV113 is a major virulence determinant in the natural host. Notably, ORFV113 represents the first viral protein that modulates p38 signaling via interaction with LPA(1) receptor. Author summaryViruses have evolved mechanisms to subvert critical cellular signaling pathways that regulate diverse cellular functions. LPA signaling in skin is known to affect a wide range of cellular functions, including cell differentiation, migration, proliferation and chemotaxis, and it has been implicated in innate immune responses, inflammation and wound healing. Here, we show that ORFV113, a protein unique to parapoxviruses, interacts with the G protein coupled receptor, Lysophosphatidic acid receptor 1 (LPA(1)) enhancing p38 phosphorylation in ORFV-infected cells in vitro and keratinocytes in vivo, and in cells transiently expressing ORFV113 or treated with soluble ORFV113. p38 signaling markedly affects ORFV plaque formation and replication in infected cells. When ORFV113 is deleted from the viral genome, the resulting virus loses the ability to replicate to high titers and to induce gross lesions in the skin of sheep. Notably, ORFV113 represents the first viral protein that modulates p38 signaling by interacting with LPA(1) receptor.