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 Tiwari, Han Pil Choi, Takeshi Matsuzawa, Marc Pypaert, John D. MacMicking

Research output: Contribution to journalArticle

76 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)907-917
Number of pages11
JournalNature Immunology
Volume10
Issue number8
DOIs
StatePublished - 2009
Externally publishedYes

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GTP Phosphohydrolases
Mycobacterium
Immunity
Phagosomes
Phosphatidylinositol 3-Kinases
Class I Phosphatidylinositol 3-Kinases
Membranes
Macrophages
Lipids
Infection
Mycobacterium tuberculosis
Innate Immunity
Vertebrates
phosphatidylinositol 3,4-diphosphate
phosphatidylinositol 3,4,5-triphosphate

ASJC Scopus subject areas

  • Immunology

Cite this

Targeting of the GTPase Irgm1 to the phagosomal membrane via PtdIns(3,4)P2 and PtdIns(3,4,5)P3 promotes immunity to mycobacteria. / Tiwari, Sangeeta; Choi, Han Pil; Matsuzawa, Takeshi; Pypaert, Marc; MacMicking, John D.

In: Nature Immunology, Vol. 10, No. 8, 2009, p. 907-917.

Research output: Contribution to journalArticle

Tiwari, Sangeeta ; Choi, Han Pil ; Matsuzawa, Takeshi ; Pypaert, Marc ; MacMicking, John D. / Targeting of the GTPase Irgm1 to the phagosomal membrane via PtdIns(3,4)P2 and PtdIns(3,4,5)P3 promotes immunity to mycobacteria. In: Nature Immunology. 2009 ; Vol. 10, No. 8. pp. 907-917.
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