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Published on: December 21, 2019
AAA ATPase p97/VCP is essential for TRIM21-mediated virus neutralization
Felix Hauler1, Donna L Mallery, William A McEwan
1Protein and Nucleic Acid Chemistry Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, CB2 0QH, United Kingdom.
Summary
Tripartite motif-containing 21 (TRIM21) utilizes the ATPase p97/valosin-containing protein (VCP) to degrade large viral capsids for intracellular neutralization. VCP is essential for this process, highlighting its role in antiviral immunity.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Tripartite motif-containing 21 (TRIM21) is a cytosolic receptor mediating antibody-dependent intracellular antiviral defense.
- TRIM21 targets antibody-bound virions for proteasomal degradation, but the mechanism for degrading large viral capsids remains unclear.
Purpose of the Study:
- To elucidate the host factors involved in the proteasomal degradation of viral capsids mediated by TRIM21.
- To investigate the role of the ATPase p97/valosin-containing protein (VCP) in TRIM21-dependent antiviral immunity.
Main Methods:
- Depletion and catalytic inhibition of VCP in cellular models.
- Assessment of viral capsid degradation and neutralization efficiency.
- Comparison of viral capsid degradation with IgG Fc degradation.
Main Results:
- Depletion or inhibition of VCP significantly impaired viral capsid degradation and reduced antibody-mediated neutralization.
- VCP activity was required concurrently with proteasome function for capsid degradation.
- Intracellular IgG Fc fragments were degraded independently of VCP, suggesting substrate-specific requirements.
Conclusions:
- The ATPase VCP is a crucial host factor required for the TRIM21-mediated degradation of large viral capsids.
- VCP's segregase and unfoldase activities are implicated in overcoming the challenge of degrading bulky viral substrates.
- These findings reveal a novel mechanism of antiviral immunity involving VCP in intracellular pathogen clearance.
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