Phagosomal membrane targeting of Irgm1 via PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3) promotes mycobacterial immunity

Vertebrate immunity to infection enlists a new family of 47 kDa 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 Irgm1 targets the mycobacterial phagosome (PG) via lipid-mediated interactions with phosphoinositide-3,4-bisphosphate (PtdIns[3,4]P(2)) and PtdIns(3,4,5)P(3). An isolated Irgm1 amphipathic helix conferred lipid binding in vitro and in vivo. Mutations in this region blocked PG recruitment and failed to complement the antimicrobial defect in Irgm1(-/-) macrophages. PtdIns(3,4,5)P(3) removal or class I phosphoinositide-3-OH kinase (PI(3)K) inhibition mimicked this effect in wild-type cells. Irgm1-PI(3)K co-operation further facilitated Irgm1 engaging its fusogenic effectors at the site of infection, thereby ensuring pathogen-directed responses during innate immunity.