Article abstract
Nature Immunology 10, 907 - 917 (2009)
Published online: 20 July 2009 | doi:10.1038/ni.1759
Targeting of the GTPase Irgm1 to the phagosomal membrane via PtdIns(3,4)P2 and PtdIns(3,4,5)P3 promotes immunity to mycobacteria
Sangeeta Tiwari1, Han-Pil Choi1, Takeshi Matsuzawa1,3, Marc Pypaert2,4 & John D MacMicking1
Abstract
Vertebrate immunity to infection enlists a newly identified family of 47-kilodalton immunity-related GTPases (IRGs). One IRG in particular, Irgm1, is essential for macrophage host defense against phagosomal pathogens, including Mycobacterium tuberculosis (Mtb). Here we show that Irgm1 targets the mycobacterial phagosome through lipid-mediated interactions with phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2) and PtdIns(3,4,5)P3. An isolated Irgm1 amphipathic helix conferred lipid binding in vitro and in vivo. Substitutions in this region blocked phagosome recruitment and failed to complement the antimicrobial defect in Irgm1-/- macrophages. Removal of PtdIns(3,4,5)P3 or inhibition of class I phosphatidylinositol-3-OH kinase (PI(3)K) mimicked this effect in wild-type cells. Cooperation between Irgm1 and PI(3)K further facilitated the engagement of Irgm1 with its fusogenic effectors at the site of infection, thereby ensuring pathogen-directed responses during innate immunity.
- Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
- Department of Cell Biology, Center for Cell and Molecular Imaging, Yale University School of Medicine, New Haven, Connecticut, USA.
- Present address: Department of Veterinary Public Health, Division of Veterinary Science, Graduate School of Life and Environmental Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Japan.
- Deceased.
Correspondence to: John D MacMicking1 e-mail: john.macmicking@yale.edu
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