Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins.
Conference Paper
Many microbes create and maintain pathogen-containing vacuoles (PVs) as an intracellular niche permissive for microbial growth and survival. The destruction of PVs by IFNγ-inducible guanylate binding protein (GBP) and immunity-related GTPase (IRG) host proteins is central to a successful immune response directed against numerous PV-resident pathogens. However, the mechanism by which IRGs and GBPs cooperatively detect and destroy PVs is unclear. We find that host cell priming with IFNγ prompts IRG-dependent association of Toxoplasma- and Chlamydia-containing vacuoles with ubiquitin through regulated translocation of the E3 ubiquitin ligase tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6). This initial ubiquitin labeling elicits p62-mediated escort and deposition of GBPs to PVs, thereby conferring cell-autonomous immunity. Hypervirulent strains of Toxoplasma gondii evade this process via specific rhoptry protein kinases that inhibit IRG function, resulting in blockage of downstream PV ubiquitination and GBP delivery. Our results define a ubiquitin-centered mechanism by which host cells deliver GBPs to PVs and explain how hypervirulent parasites evade GBP-mediated immunity.
Full Text
Duke Authors
Cited Authors
- Haldar, AK; Foltz, C; Finethy, R; Piro, AS; Feeley, EM; Pilla-Moffett, DM; Komatsu, M; Frickel, E-M; Coers, J
Published Date
- October 13, 2015
Published In
Volume / Issue
- 112 / 41
Start / End Page
- E5628 - E5637
PubMed ID
- 26417105
Pubmed Central ID
- PMC4611635
Electronic International Standard Serial Number (EISSN)
- 1091-6490
Digital Object Identifier (DOI)
- 10.1073/pnas.1515966112
Conference Location
- United States