title: TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation.
abstract: Autophagy is a fundamental biological process of the eukaryotic cell contributing to diverse cellular and physiological functions including cell-autonomous defense against intracellular pathogens. Here, we screened the Rab family of membrane trafficking regulators for effects on autophagic elimination of Mycobacterium tuberculosis var. bovis BCG and found that Rab8b and its downstream interacting partner, innate immunity regulator TBK-1, are required for autophagic elimination of mycobacteria in macrophages. TBK-1 was necessary for autophagic maturation. TBK-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on Ser-403, a residue essential for its role in autophagic clearance. A key proinflammatory cytokine, IL-1β, induced autophagy leading to autophagic killing of mycobacteria in macrophages, and this IL-1β activity was dependent on TBK-1. Thus, TBK-1 is a key regulator of immunological autophagy and is responsible for the maturation of autophagosomes into lytic bactericidal organelles.
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: Manohar
authors.initials: M
authors.lastname: Pilli
authors.forename: John
authors.initials: J
authors.lastname: Arko-Mensah
authors.forename: Marisa
authors.initials: M
authors.lastname: Ponpuak
authors.forename: Esteban
authors.initials: E
authors.lastname: Roberts
authors.forename: Sharon
authors.initials: S
authors.lastname: Master
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mandell
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dupont
authors.forename: Wojciech
authors.initials: W
authors.lastname: Ornatowski
authors.forename: Shanya
authors.initials: S
authors.lastname: Jiang
authors.forename: Steven B
authors.initials: SB
authors.lastname: Bradfute
authors.forename: Jack-Ansgar
authors.initials: JA
authors.lastname: Bruun
authors.forename: Tom Egil
authors.initials: TE
authors.lastname: Hansen
authors.forename: Terje
authors.initials: T
authors.lastname: Johansen
authors.forename: Vojo
authors.initials: V
authors.lastname: Deretic
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000276:immunology*; D000071193:Autophagy-Related Protein 7; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D009163:Mycobacterium bovis / Q000276:immunology; D010588:Phagosomes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; D012694:Serine / Q000276:immunology / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502661:Atg7 protein, mouse; D006360:Heat-Shock Proteins; D053583:Interleukin-1beta; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D049452:Green Fluorescent Proteins; D012694:Serine; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C576245:Rab8b protein, mouse; D020691:rab GTP-Binding Proteins; D000071193:Autophagy-Related Protein 7