Host AAA-ATPase VCP/p97 lyses ubiquitinated intracellular bacteria as an innate antimicrobial defence.

Summary

This mechanistic study identifies VCP/p97 as a host AAA-ATPase that mechanically extracts ubiquitinated bacterial surface proteins, leading to membrane lysis and pathogen killing, and demonstrates protection from fatal sepsis in mice. It reveals a distinct, proteostasis-linked innate antimicrobial pathway with translational potential for host-directed therapies.

Key Findings

• VCP/p97 binds cytosol-exposed ubiquitinated bacteria (S. pneumoniae, S. Typhimurium, S. pyogenes) and requires D2 ATPase activity to reduce intracellular bacterial loads.
• Optical trapping, MD simulations, and in vitro reconstitution show p97 extracts ubiquitinated surface proteins (BgaA, PspA) from S. pneumoniae, causing membrane lysis.
• In mice, p97 limits S. pneumoniae proliferation and protects from fatal sepsis, revealing a host proteostasis-linked antimicrobial defense.

Clinical Implications

While preclinical, augmenting p97 activity or mimicking its bacterial protein-extraction mechanism could inspire host-directed adjuvants to combat intracellular pathogens and reduce reliance on antibiotics.

Limitations

• Preclinical study; human translational efficacy and safety remain untested
• Dependence on ubiquitination of bacterial surface proteins may vary by pathogen and host context

Future Directions

Define pharmacologic or genetic strategies to modulate p97 activity in vivo, map ubiquitinated bacterial substrates across pathogens, and evaluate host-directed adjuvants in infection models and early-phase human studies.