title: Phosphoinositides in phagolysosome and autophagosome biogenesis.
abstract: Interconversions of phosphoinositides play a pivotal role during phagocytosis and at the subsequent stages of phagosomal maturation into the phagolysosome. Several model systems have been used to study the role of phosphoinositides in phagosomal membrane remodelling. These include phagosomes formed by inanimate objects such as latex beads, or pathogenic bacteria, e.g. Mycobacterium tuberculosis. The latter category provides naturally occurring tools to dissect membrane trafficking processes governing phagolysosome biogenesis. M. tuberculosis persists in infected macrophages by blocking Rab conversion and affecting Rab effectors. One of the major Rab effectors involved in this process is the type III phosphatidylinositol 3-kinase hVPS34. The lipid kinase hVPS34 and its enzymatic product PtdIns3P are critical for the default pathway of phagosomal maturation into phagolysosomes. Mycobacteria block PtdIns3P production and thus arrest phagosomal maturation. PtdIns3P is also critical for the process of autophagy, recently recognized as an effector of innate immunity defenses. Induction of autophagy by pharmacological, physiological, or immunological means, overcomes mycobacterial phagosome maturation block in a PtdIns3P generation dependent manner and eliminates intracellular M. tuberculosis. PtdIns3P and PtdIns3P-dependent processes represent an important cellular nexus where fundamental trafficking processes, disease causing host-pathogen interactions, and innate and adaptive immunity defense mechanisms meet.
authors.affiliation: Department of Molecular Genetics, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE Albuquerque, NM 87131-001, USA. vderetic@salud.unm.edu
authors.forename: Vojo
authors.initials: V
authors.lastname: Deretic
authors.forename: Sudha
authors.initials: S
authors.lastname: Singh
authors.forename: Sharon
authors.initials: S
authors.lastname: Master
authors.forename: George
authors.initials: G
authors.lastname: Kyei
authors.forename: Alex
authors.initials: A
authors.lastname: Davis
authors.forename: John
authors.initials: J
authors.lastname: Naylor
authors.forename: Sergio
authors.initials: S
authors.lastname: de Haro
authors.forename: James
authors.initials: J
authors.lastname: Harris
authors.forename: Monica
authors.initials: M
authors.lastname: Delgado
authors.forename: Esteban
authors.initials: E
authors.lastname: Roberts
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vergne
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000502:physiology; D010587:Phagocytosis / Q000502:physiology; D010588:Phagosomes / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000276:immunology / Q000378:metabolism; D010716:Phosphatidylinositols / Q000276:immunology / Q000378:metabolism*
chemical_list: D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; C055525:phosphatidylinositol 3-phosphate