The lumpy skin disease virus protein LSDV003 regulates MHC-I trafficking and surface expression
4 affiliations
- 1State Key Laboratory of Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences
- 2Gansu Province Research Center for Basic Disciplines of Pathogen Biology
- 3College of Veterinary Medicine, South China Agricultural University
- 4Department of Infectious Diseases, Medical Research Institute, Taikang Center for Life and Medical Sciences, State Key Laboratory for Virology and Biosafety, Zhongnan Hospital of Wuhan University, Wuhan University
Abstract
Lumpy skin disease (LSD) is a severe transboundary disease of cattle caused by lumpy skin disease virus (LSDV), which is highly transmissible and responsible for substantial economic losses worldwide. Although cellular immune responses are critical for controlling poxvirus infections, the viral strategies used by LSDV to evade cytotoxic T-cell immunity remain poorly understood. In this study, we demonstrate that LSDV infection markedly downregulates major histocompatibility complex class I (MHC-I) surface expression in host cells. Screening of LSDV-encoded proteins identified LSDV003 as a key viral factor responsible for MHC-I downregulation. Mechanistically, LSDV003 interacts with both the MHC-I heavy chain and β2-microglobulin and mediates endoplasmic reticulum (ER) retention of MHC-I via a C-terminal HNEL motif, thereby preventing its transport to the cell surface. Mutational analyses demonstrated that disruption of the HNEL motif impaired the ability of LSDV003 to alter MHC-I localization and surface expression. Furthermore, an LSDV003-deficient virus exhibited a markedly reduced capacity to suppress MHC-I surface expression. Collectively, these findings identify LSDV003 as a viral regulator of MHC-I trafficking and reveal a mechanism by which LSDV modulates host immune recognition.
IMPORTANCE: Lumpy skin disease is a highly contagious viral disease of cattle that has spread rapidly across Afro-Eurasia and causes major economic losses. However, the mechanisms used by lumpy skin disease virus to evade host immune defenses remain incompletely understood. In this study, we identify a previously unrecognized lumpy skin disease virus protein, LSDV003, that reduces the surface expression of major histocompatibility complex class I molecules in infected cells. We found that LSDV003 prevents these molecules from leaving the endoplasmic reticulum by using a C-terminal retention motif, thereby altering their normal intracellular trafficking. An LSDV003-deficient virus showed a reduced ability to suppress major histocompatibility complex class I surface expression during infection. These findings reveal an important immune evasion strategy used by lumpy skin disease virus and highlight LSDV003 as a potential target for improved vaccines and antiviral approaches to control this economically important disease.
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BibTeX
@article{yang2026lumpy,
title = {{The lumpy skin disease virus protein LSDV003 regulates MHC-I trafficking and surface expression}},
author = {Yang Yang and Lu-yao Gao and Ai-Min Guo and Huai-Jie Jia and Mi Li and Xin Wu and Hong-Bing Shu and Tian Xia},
journal = {mBio},
year = {2026},
month = oct,
doi = {10.1128/mbio.02359-26},
url = {https://journals.asm.org/doi/10.1128/mbio.02359-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The lumpy skin disease virus protein LSDV003 regulates MHC-I trafficking and surface expression
AU - Yang Yang
AU - Lu-yao Gao
AU - Ai-Min Guo
AU - Huai-Jie Jia
AU - Mi Li
AU - Xin Wu
AU - Hong-Bing Shu
AU - Tian Xia
PY - 2026
DA - 2026/10/22
JO - mBio
DO - 10.1128/mbio.02359-26
UR - https://journals.asm.org/doi/10.1128/mbio.02359-26
AB - Lumpy skin disease (LSD) is a severe transboundary disease of cattle caused by lumpy skin disease virus (LSDV), which is highly transmissible and responsible for substantial economic losses worldwide. Although cellular immune responses are critical for controlling poxvirus infections, the viral strategies used by LSDV to evade cytotoxic T-cell immunity remain poorly understood. In this study, we demonstrate that LSDV infection markedly downregulates major histocompatibility complex class I (MHC-I) surface expression in host cells. Screening of LSDV-encoded proteins identified LSDV003 as a key viral factor responsible for MHC-I downregulation. Mechanistically, LSDV003 interacts with both the MHC-I heavy chain and β2-microglobulin and mediates endoplasmic reticulum (ER) retention of MHC-I via a C-terminal HNEL motif, thereby preventing its transport to the cell surface. Mutational analyses demonstrated that disruption of the HNEL motif impaired the ability of LSDV003 to alter MHC-I localization and surface expression. Furthermore, an LSDV003-deficient virus exhibited a markedly reduced capacity to suppress MHC-I surface expression. Collectively, these findings identify LSDV003 as a viral regulator of MHC-I trafficking and reveal a mechanism by which LSDV modulates host immune recognition. IMPORTANCE: Lumpy skin disease is a highly contagious viral disease of cattle that has spread rapidly across Afro-Eurasia and causes major economic losses. However, the mechanisms used by lumpy skin disease virus to evade host immune defenses remain incompletely understood. In this study, we identify a previously unrecognized lumpy skin disease virus protein, LSDV003, that reduces the surface expression of major histocompatibility complex class I molecules in infected cells. We found that LSDV003 prevents these molecules from leaving the endoplasmic reticulum by using a C-terminal retention motif, thereby altering their normal intracellular trafficking. An LSDV003-deficient virus showed a reduced ability to suppress major histocompatibility complex class I surface expression during infection. These findings reveal an important immune evasion strategy used by lumpy skin disease virus and highlight LSDV003 as a potential target for improved vaccines and antiviral approaches to control this economically important disease.
SN - 2150-7511
ER -