Open AccessThe novel ORFV protein ORFV113 activates LPA-p38 signaling
Author(s) -
Sushil Khatiwada,
G. Delhon,
Sabal Chaulagain,
Daniel L. Rock
Publication year - 2021
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1009971
Subject(s) - biology , microbiology and biotechnology , phosphorylation , p38 mitogen activated protein kinases , signal transduction , lysophosphatidic acid , innate immune system , protein kinase a , viral replication , chemotaxis , kinase , receptor , immune system , virus , virology , immunology , biochemistry
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-IA82Δ113) 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-IA82Δ113 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.