Mycobacterium tuberculosis induces the miR-33 locus to reprogram autophagy and host lipid metabolism
RNA Therapeutics Institute; Department of Biochemistry and Molecular Pharmacology
Biochemistry, Biophysics, and Structural Biology | Cell and Developmental Biology | Genetics and Genomics | Immunology and Infectious Disease | Therapeutics
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.
Bacterial immune evasion, Innate immunity, Lipids
DOI of Published Version
Nat Immunol. 2016 Jun;17(6):677-86. doi: 10.1038/ni.3434. Epub 2016 Apr 18. Link to article on publisher's site
Ouimet M, Cecchini K, Zamore PD, Moore KJ. (2016). Mycobacterium tuberculosis induces the miR-33 locus to reprogram autophagy and host lipid metabolism. RNA Therapeutics Institute Publications. https://doi.org/10.1038/ni.3434. Retrieved from https://escholarship.umassmed.edu/rti_pubs/15