The novel ORFV protein ORFV113 activates LPA-p38 signaling

Authors

Sushil Khatiwad, University of Illinois at Urbana-Champaign
Gustavo Delho, University of Nebraska-LincolnFollow
Sabal Chaulagai, University of Illinois at Urbana-Champaign
Daniel L. Rock, University of Illinois at Urbana-ChampaignFollow

ORCID IDs

Daniel L. Rock https://orcid.org/0000-0002-8548-3317

Document Type

Article

Date of this Version

10-6-2021

Citation

Khatiwada S, Delhon G, Chaulagain S, Rock DL (2021) The novel ORFV protein ORFV113 activates LPA-p38 signaling. PLoS Pathog 17(10): e1009971. https://doi.org/10.1371/journal. ppat.1009971

Comments

© 2021 Khatiwada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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 (LPA₁). Consistent with its interaction with LPA₁, 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 (OVIA82Δ113) 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 LPA₁ expression was knocked down and in cells treated with LPA₁ 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 LPA₁ receptor.