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Published on: January 7, 2019
The conserved poxvirus membrane entry-fusion apparatus component OPG147 targets MITA/STING for immune evasion
Xue-Mei Yi1, Mi Li1, Su-Yun Wang2
1Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Hubei Provincial Research Center for Basic Biological Sciences, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China.
Abstract:
Monkeypox virus (MPXV) causes severe diseases in immunocompromised individuals. How MPXV evades the host defense remain enigmatic. We performed expression screens and identified MPXV OPG147, a membrane fusion machinery protein, as an inhibitor of cGAS-MITA/STING-mediated innate immunity. OPG147 from other poxviruses including the prototypic vaccinia virus (VACV) shows similar functions. OPG147 is associated with MITA/STING and STIM1, a calcium sensor that retains MITA/STING in the ER. OPG147 does not block cGAMP binding to MITA, but inhibits its ISGylation, dimerization/oligomerization and trafficking, thereby suppressing its activation. Mutation of VACV OPG147 F55/T116/T117 to alanine (VACVOPG147/3A) has no effects on its infection and replication, but induces higher innate immune response compared with wild-type VACV in cells and mice. VACVOPG147/3A infection also results in lower viral loads and decreased disease severity in mice. Our findings suggest that OPG147 contributes to immune evasion and is a virulence factor of poxviruses.
Insights
Monkeypox virus uses OPG147 protein to evade host immunity by blocking the cGAS-MITA/STING pathway. Mutating this protein enhances immune response and reduces disease severity in mice.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Monkeypox virus (MPXV) poses a significant threat, especially to immunocompromised individuals.
- Mechanisms by which MPXV evades host immune defenses are not fully understood.
Purpose of the Study:
- To identify MPXV proteins involved in inhibiting host innate immunity.
- To elucidate the function of MPXV OPG147 in immune evasion.
Main Methods:
- Expression screening to identify immune inhibitors.
- Co-immunoprecipitation to study protein interactions.
- Functional assays to assess innate immune pathway activation.
- In vivo studies using a mouse model.
Main Results:
- MPXV OPG147, a membrane fusion protein, inhibits cGAS-MITA/STING-mediated innate immunity.
- OPG147 interacts with MITA/STING and STIM1, retaining MITA/STING in the endoplasmic reticulum.
- OPG147 suppresses MITA/STING activation by inhibiting ISGylation, dimerization, and trafficking, but not cGAMP binding.
- Mutating OPG147 in vaccinia virus (VACV) enhances innate immune response, reduces viral load, and decreases disease severity in mice.
Conclusions:
- OPG147 is a viral virulence factor contributing to poxvirus immune evasion.
- Targeting OPG147 could be a strategy to combat poxvirus infections.
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