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Nat Immunol. 2016 Jun;17(6):677-86. doi: 10.1038/ni.3434. Epub 2016 Apr 18.

Mycobacterium tuberculosis induces the miR-33 locus to reprogram autophagy and host lipid metabolism.

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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.
Division of Infectious Diseases and Immunology, Department of Medicine, New York University Medical Center, New York, New York, USA.
University of Ottawa Heart Institute and Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
Department of Clinical Medicine, School of Medicine, Trinity College, Dublin, Ireland.
RNA Therapeutics Institute, Howard Hughes Medical Institute, and Department of Biochemistry &Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.


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.

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