title: Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria.
abstract: IRGM, a human immunity-related GTPase, confers autophagic defence against intracellular pathogens by an unknown mechanism. Here, we report an unexpected mode of IRGM action. IRGM demonstrated differential affinity for the mitochondrial lipid cardiolipin, translocated to mitochondria, affected mitochondrial fission and induced autophagy. Mitochondrial fission was necessary for autophagic control of intracellular mycobacteria by IRGM. IRGM influenced mitochondrial membrane polarization and cell death. Overexpression of IRGMd, but not IRGMb splice isoforms, caused mitochondrial depolarization and autophagy-independent, but Bax/Bak-dependent, cell death. By acting on mitochondria, IRGM confers autophagic protection or cell death, explaining IRGM action both in defence against tuberculosis and in the damaging inflammation caused by Crohn's disease.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131 USA.
authors.forename: Sudha B
authors.initials: SB
authors.lastname: Singh
authors.forename: Wojciech
authors.initials: W
authors.lastname: Ornatowski
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vergne
authors.forename: John
authors.initials: J
authors.lastname: Naylor
authors.forename: Monica
authors.initials: M
authors.lastname: Delgado
authors.forename: Esteban
authors.initials: E
authors.lastname: Roberts
authors.forename: Marisa
authors.initials: M
authors.lastname: Ponpuak
authors.forename: Sharon
authors.initials: S
authors.lastname: Master
authors.forename: Manohar
authors.initials: M
authors.lastname: Pilli
authors.forename: Eileen
authors.initials: E
authors.lastname: White
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.forename: Vojo
authors.initials: V
authors.lastname: Deretic
mesh_terms: D000818:Animals; D001343:Autophagy; D002308:Cardiolipins / Q000378:metabolism; D002460:Cell Line; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism
chemical_list: D002308:Cardiolipins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D020033:Protein Isoforms; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C513539:IRGM protein, human; C110768:DNM1L protein, human; D034281:Dynamins