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Updated: Apr 2, 2026

In-vitro Reconstitution of Bacterial Ubiquitination and VCP/p97-mediated Elimination
07:58

In-vitro Reconstitution of Bacterial Ubiquitination and VCP/p97-mediated Elimination

Published on: January 2, 2026

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Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins

Arun K Haldar1, Clémence Foltz2, Ryan Finethy1

  • 1Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, NC 27710;

Proceedings of the National Academy of Sciences of the United States of America
|September 30, 2015
PubMed

Insights

Host cells use ubiquitin to target guanylate binding proteins (GBPs) to pathogen-containing vacuoles (PVs), enabling immunity. Toxoplasma gondii evades this by inhibiting IRG proteins, blocking GBP delivery and promoting parasite survival.

Area of Science:

  • Cellular and Molecular Immunology
  • Host-Pathogen Interactions
  • Ubiquitin Signaling

Background:

  • Pathogen-containing vacuoles (PVs) are intracellular niches exploited by microbes.
  • Immune responses involving guanylate binding proteins (GBPs) and immunity-related GTPases (IRGs) are crucial for eliminating PV-resident pathogens.
  • The precise mechanism of cooperative PV detection and destruction by IRGs and GBPs remains largely unknown.

Purpose of the Study:

  • To elucidate the mechanism by which IRGs and GBPs cooperate to detect and destroy pathogen-containing vacuoles.
  • To understand how host cells deliver GBPs to PVs for cell-autonomous immunity.
  • To investigate how virulent pathogens evade GBP-mediated immune responses.

Main Methods:

  • IFNγ priming of host cells.
  • Analysis of ubiquitin association with PVs.
  • Tracking translocation of E3 ubiquitin ligase TRAF6.
  • Investigating p62-mediated GBP escort and deposition.
  • Studying the role of Toxoplasma gondii rhoptry protein kinases.

Main Results:

  • IFNγ priming induces IRG-dependent ubiquitination of PVs via TRAF6 translocation.
  • Ubiquitin labeling recruits p62, which escorts and deposits GBPs to PVs, establishing cell-autonomous immunity.
  • Hypervirulent Toxoplasma gondii utilizes rhoptry kinases to inhibit IRG function, blocking PV ubiquitination and GBP delivery.

Conclusions:

  • A ubiquitin-centered mechanism facilitates GBP delivery to PVs, mediating host defense.
  • Toxoplasma gondii has evolved a strategy to evade GBP-mediated immunity by disrupting the ubiquitin-dependent PV targeting pathway.
Keywords:
ChlamydiaGBPsToxoplasmaimmunity-related GTPaseinterferon

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