@article{5de8f34b081e4c6fb5a548f30f905498,
title = "Human GBP1 is a microbe-specific gatekeeper of macrophage apoptosis and pyroptosis",
abstract = "The guanylate binding protein (GBP) family of interferon-inducible GTPases promotes antimicrobial immunity and cell death. During bacterial infection, multiple mouse Gbps, human GBP2, and GBP5 support the activation of caspase-1-containing inflammasome complexes or caspase-4 which trigger pyroptosis. Whether GBPs regulate other forms of cell death is not known. The apicomplexan parasite Toxoplasma gondii causes macrophage death through unidentified mechanisms. Here we report that Toxoplasma-induced death of human macrophages requires GBP1 and its ability to target Toxoplasma parasitophorous vacuoles through its GTPase activity and prenylation. Mechanistically, GBP1 promoted Toxoplasma detection by AIM2, which induced GSDMD-independent, ASC-, and caspase-8-dependent apoptosis. Identical molecular determinants targeted GBP1 to Salmonella-containing vacuoles. GBP1 facilitated caspase-4 recruitment to Salmonella leading to its enhanced activation and pyroptosis. Notably, GBP1 could be bypassed by the delivery of Toxoplasma DNA or bacterial LPS into the cytosol, pointing to its role in liberating microbial molecules. GBP1 thus acts as a gatekeeper of cell death pathways, which respond specifically to infecting microbes. Our findings expand the immune roles of human GBPs in regulating not only pyroptosis, but also apoptosis.",
keywords = "Salmonella Typhimurium, Toxoplasma gondii, apoptosis, caspases, pyroptosis",
author = "Daniel Fisch and Hironori Bando and Barbara Clough and Veit Hornung and Masahiro Yamamoto and Shenoy, {Avinash R.} and Frickel, {Eva Maria}",
note = "Funding Information: We would like to thank Monique Bunyan for preparing STAg, Asha Patel for help with flow cytometry, Max Gutierrez and Daniel Greenwood for sourcing and advising MDM preparation, Anna Coussens and Nashied Peton for advice on MDM differentiation and transfection, Julia Sanchez-Garrido for help in optimizing immunoblots and advice on siRNAs, the Crick High-throughput screening (HTS) STP for help in performing the Incucyte time course experiments, the Crick Genomics and Equipment Park STP for performing sequencing and DNA minipreps for cloning, and J{\"o}rn Coers for critical reading of the article. We thank all members of the Frickel and the Shenoy laboratories for productive discussion and Crick Core facilities for assistance in the project. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001076), the UK Medical Research Council (FC001076), and the Wellcome Trust (FC001076). EMF was supported by a Wellcome Trust Career Development Fellowship (091664/B/10/Z). DF was supported by a Boehringer Ingelheim Fonds PhD fellowship. ARS would like to acknowledge support from the MRC (MR/P022138/1) and Wellcome Trust (108246/Z/15/Z). MY was supported by the Research Program on Emerging and Re-emerging Infectious Diseases (JP18fk0108047) and Japanese Initiative for Progress of Research on Infectious Diseases for global Epidemic (JP18fk0108046) from Agency for Medical Research and Development (AMED). HB was supported by Grant-in-Aid for Scientific Research on Innovative Areas (17K15677) from Ministry of Education, Culture, Sports, Science, and Technology. Publisher Copyright: {\textcopyright} 2019 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2019",
month = jul,
day = "1",
doi = "10.15252/embj.2018100926",
language = "English",
volume = "38",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "13",
}