Pseudorabies virus pUL40 drives inflammatory signaling through competitive hijacking of EphA2 from the Akt–EphA2 interaction
Abstract
Herpesvirus infection triggers excessive inflammation, contributing to tissue injury and disease severity, but the underlying drivers remain unclear. Here we identify EphA2 as a critical mediator of pseudorabies virus (PRV)-induced inflammatory response. Genetic or pharmacological inhibition of EphA2 reduced TNF-α production in PRV-infected cells and mice, alleviated liver and lung damage, and improved mice survival. Mechanistically, PRV infection promoted EphA2 phosphorylation at Ser-897, which activated NF-κB and MAPK pathways to drive TNF-α production. The PRV tegument protein UL40 directly bound the EphA2 kinase domain (residues 697–901), a region that also interacts with Akt. Unexpectedly, Akt acted as a negative regulator of inflammation, as its knockdown exacerbated cytokine production. UL40 competitively disrupted the constitutive EphA2–Akt complex in a time-dependent manner, relieving Akt-mediated restraint on EphA2 S897 phosphorylation. Accordingly, a UL40-deficient PRV mutant failed to enhance S897 phosphorylation, elicited lower inflammatory responses, and showed attenuated virulence in mice. Collectively, our findings reveal a proviral strategy whereby PRV UL40 hijacks EphA2 to counteract an intrinsic Akt-dependent inhibitory pathway. This UL40–EphA2–Akt cascade is a critical determinant of virus-induced inflammation, and EphA2 S897 represents a potential therapeutic target for mitigating alphaherpesvirus immunopathology.
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BibTeX
@article{tian2026pseudorabies,
title = {{Pseudorabies virus pUL40 drives inflammatory signaling through competitive hijacking of EphA2 from the Akt–EphA2 interaction}},
author = {Yutong Tian and Hang Yin and Jiaxiang Fu and Qingqing Yang and Ru Yan and Yuqing Li and Chao Ye and Rendong Fang},
journal = {Veterinary Research},
year = {2026},
month = aug,
doi = {10.1186/s13567-026-01829-4},
url = {https://hal.science/hal-05731885v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Pseudorabies virus pUL40 drives inflammatory signaling through competitive hijacking of EphA2 from the Akt–EphA2 interaction
AU - Yutong Tian
AU - Hang Yin
AU - Jiaxiang Fu
AU - Qingqing Yang
AU - Ru Yan
AU - Yuqing Li
AU - Chao Ye
AU - Rendong Fang
PY - 2026
DA - 2026/08/31
JO - Veterinary Research
DO - 10.1186/s13567-026-01829-4
UR - https://hal.science/hal-05731885v1
AB - Herpesvirus infection triggers excessive inflammation, contributing to tissue injury and disease severity, but the underlying drivers remain unclear. Here we identify EphA2 as a critical mediator of pseudorabies virus (PRV)-induced inflammatory response. Genetic or pharmacological inhibition of EphA2 reduced TNF-α production in PRV-infected cells and mice, alleviated liver and lung damage, and improved mice survival. Mechanistically, PRV infection promoted EphA2 phosphorylation at Ser-897, which activated NF-κB and MAPK pathways to drive TNF-α production. The PRV tegument protein UL40 directly bound the EphA2 kinase domain (residues 697–901), a region that also interacts with Akt. Unexpectedly, Akt acted as a negative regulator of inflammation, as its knockdown exacerbated cytokine production. UL40 competitively disrupted the constitutive EphA2–Akt complex in a time-dependent manner, relieving Akt-mediated restraint on EphA2 S897 phosphorylation. Accordingly, a UL40-deficient PRV mutant failed to enhance S897 phosphorylation, elicited lower inflammatory responses, and showed attenuated virulence in mice. Collectively, our findings reveal a proviral strategy whereby PRV UL40 hijacks EphA2 to counteract an intrinsic Akt-dependent inhibitory pathway. This UL40–EphA2–Akt cascade is a critical determinant of virus-induced inflammation, and EphA2 S897 represents a potential therapeutic target for mitigating alphaherpesvirus immunopathology.
SN - 0928-4249
SN - 1297-9716
ER -