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Updated: Jul 19, 2025
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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
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ADAM17 targeting by human cytomegalovirus remodels the cell surface proteome to simultaneously regulate multiple
Anzelika Rubina1, Mihil Patel1, Katie Nightingale2
1Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
Summary
Human cytomegalovirus (HCMV) subverts immunity by targeting the protease ADAM17, stabilizing 114 proteins. This viral mechanism broadly regulates immune responses and NK cell inhibition.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Human cytomegalovirus (HCMV) establishes lifelong infections by evading host immune defenses.
- Tumor necrosis factor receptor 2 (TNFR2), a target of the pro-inflammatory cytokine TNFα, is upregulated during HCMV infection.
Purpose of the Study:
- To elucidate the mechanism by which HCMV infection upregulates TNFR2.
- To investigate the role of the protease A Disintegrin And Metalloproteinase 17 (ADAM17) in HCMV-mediated immune evasion.
Main Methods:
- Proteomic plasma membrane profiling of HCMV-infected cells.
- Utilized an HCMV double-deletion mutant for UL148 and UL148D.
- Employed ADAM17 functional blockade and analyzed protein stabilization.
Main Results:
- HCMV infection impairs ADAM17 surface expression via viral proteins UL148 and UL148D.
- HCMV stabilizes 114 surface proteins in an ADAM17-dependent manner, including TNFR2, jagged1, nectin1, UL8, and UL144.
- Impaired ADAM17 function by HCMV regulates TNFα-induced cytokine responses and NK cell inhibition.
Conclusions:
- HCMV employs a novel immunoregulatory strategy by targeting the sheddase ADAM17.
- This targeting allows broad control over multiple host and viral surface proteins, modulating immune responses.
- Identified a paradigm for viral immunomodulation through the regulation of a single protease.
