Unknown

Dataset Information

0

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


ABSTRACT: Many microbes create and maintain pathogen-containing vacuoles (PVs) as an intracellular niche permissive for microbial growth and survival. The destruction of PVs by IFN?-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 IFN? 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.

SUBMITTER: Haldar AK 

PROVIDER: S-EPMC4611635 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Haldar Arun K AK   Foltz Clémence C   Finethy Ryan R   Piro Anthony S AS   Feeley Eric M EM   Pilla-Moffett Danielle M DM   Komatsu Masaki M   Frickel Eva-Maria EM   Coers Jörn J  

Proceedings of the National Academy of Sciences of the United States of America 20150928 41


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 IR  ...[more]

Similar Datasets

| S-EPMC4802790 | biostudies-other
| S-EPMC8196077 | biostudies-literature
| S-EPMC4854434 | biostudies-literature
| S-EPMC6925386 | biostudies-literature
| S-EPMC4961213 | biostudies-literature
| S-EPMC5480303 | biostudies-other
| S-EPMC6400534 | biostudies-literature
| S-EPMC5609559 | biostudies-literature
| S-EPMC186251 | biostudies-literature
| S-EPMC2745575 | biostudies-literature