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Rapid Degradation Pathways of Host Proteins During HCMV Infection Revealed by Quantitative Proteomics
Kai-Min Lin1, Katie Nightingale1, Lior Soday1
1Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
Abstract:
Human cytomegalovirus (HCMV) is an important pathogen in immunocompromised individuals and neonates, and a paradigm for viral immune evasion. We previously developed a quantitative proteomic approach that identified 133 proteins degraded during the early phase of HCMV infection, including known and novel antiviral factors. The majority were rescued from degradation by MG132, which is known to inhibit lysosomal cathepsins in addition to the proteasome. Global definition of the precise mechanisms of host protein degradation is important both to improve our understanding of viral biology, and to inform novel antiviral therapeutic strategies. We therefore developed and optimized a multiplexed comparative proteomic analysis using the selective proteasome inhibitor bortezomib in addition to MG132, to provide a global mechanistic view of protein degradation. Of proteins rescued from degradation by MG132, 34-47 proteins were also rescued by bortezomib, suggesting both that the predominant mechanism of protein degradation employed by HCMV is via the proteasome, and that alternative pathways for degradation are nevertheless important. Our approach and data will enable improved mechanistic understanding of HCMV and other viruses, and provide a shortlist of candidate restriction factors for further analysis.
Insights
Human cytomegalovirus (HCMV) infection degrades host proteins, primarily via the proteasome. This study reveals key degradation pathways, aiding understanding of viral immune evasion and antiviral strategies.
Area of Science:
- Virology
- Molecular Biology
- Proteomics
Background:
- Human cytomegalovirus (HCMV) is a significant pathogen, particularly in immunocompromised individuals and neonates.
- HCMV employs viral immune evasion strategies, including host protein degradation.
- Understanding host protein degradation mechanisms is crucial for antiviral therapies.
Purpose of the Study:
- To globally define the precise mechanisms of host protein degradation during HCMV infection.
- To differentiate between proteasomal and other degradation pathways utilized by HCMV.
- To identify novel host restriction factors targeted by HCMV.
Main Methods:
- Developed and optimized a multiplexed comparative proteomic analysis.
- Utilized selective proteasome inhibitor bortezomib and MG132 (proteasome and lysosome inhibitor).
- Quantified protein degradation and rescue from degradation upon inhibitor treatment.
Main Results:
- Identified 133 proteins degraded during early HCMV infection.
- 34-47 proteins rescued by bortezomib were also rescued by MG132, indicating proteasomal degradation is predominant.
- A subset of proteins were degraded via alternative pathways, highlighting their importance.
Conclusions:
- HCMV predominantly utilizes the proteasome for host protein degradation.
- Alternative degradation pathways are also important during HCMV infection.
- This study provides a shortlist of candidate restriction factors for further investigation into viral biology and antiviral development.
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