title: Mycobacterium tuberculosis induces the miR-33 locus to reprogram autophagy and host lipid metabolism.
abstract: Mycobacterium tuberculosis (Mtb) survives in macrophages by evading delivery to the lysosome and promoting the accumulation of lipid bodies, which serve as a bacterial source of nutrients. We found that by inducing the microRNA (miRNA) miR-33 and its passenger strand miR-33*, Mtb inhibited integrated pathways involved in autophagy, lysosomal function and fatty acid oxidation to support bacterial replication. Silencing of miR-33 and miR-33* by genetic or pharmacological means promoted autophagy flux through derepression of key autophagy effectors (such as ATG5, ATG12, LC3B and LAMP1) and AMPK-dependent activation of the transcription factors FOXO3 and TFEB, which enhanced lipid catabolism and Mtb xenophagy. These data define a mammalian miRNA circuit used by Mtb to coordinately inhibit autophagy and reprogram host lipid metabolism to enable intracellular survival and persistence in the host.
authors.affiliation: Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University Medical Center, New York, New York, USA.
authors.forename: Mireille
authors.initials: M
authors.lastname: Ouimet
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, New York University Medical Center, New York, New York, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Koster
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, New York University Medical Center, New York, New York, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Sakowski
authors.affiliation: Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University Medical Center, New York, New York, USA.
authors.forename: Bhama
authors.initials: B
authors.lastname: Ramkhelawon
authors.affiliation: Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University Medical Center, New York, New York, USA.
authors.forename: Coen
authors.initials: C
authors.lastname: van Solingen
authors.affiliation: Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University Medical Center, New York, New York, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Oldebeken
authors.affiliation: University of Ottawa Heart Institute and Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Denuja
authors.initials: D
authors.lastname: Karunakaran
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, New York University Medical Center, New York, New York, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Portal-Celhay
authors.affiliation: Department of Clinical Medicine, School of Medicine, Trinity College, Dublin, Ireland.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Sheedy
authors.affiliation: Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University Medical Center, New York, New York, USA.
authors.forename: Tathagat Dutta
authors.initials: TD
authors.lastname: Ray
authors.affiliation: RNA Therapeutics Institute, Howard Hughes Medical Institute, and Department of Biochemistry &Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Katharine
authors.initials: K
authors.lastname: Cecchini
authors.affiliation: RNA Therapeutics Institute, Howard Hughes Medical Institute, and Department of Biochemistry &Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Zamore
authors.affiliation: University of Ottawa Heart Institute and Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Katey J
authors.initials: KJ
authors.lastname: Rayner
authors.affiliation: University of Ottawa Heart Institute and Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Yves L
authors.initials: YL
authors.lastname: Marcel
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, New York University Medical Center, New York, New York, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Philips
authors.affiliation: Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University Medical Center, New York, New York, USA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002478:Cells, Cultured; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D050356:Lipid Metabolism / Q000235:genetics*; D008247:Lysosomes / Q000382:microbiology / Q000502:physiology*; D008264:Macrophages / Q000382:microbiology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014376:Tuberculosis / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D014157:Transcription Factors