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

Mireille Ouimet; Stefan Koster; Erik Sakowski; Bhama Ramkhelawon; Coen Van Solingen; Scott Oldebeken; Denuja Karunakaran; Cynthia Portal-Celhay; Frederick J. Sheedy; Tathagat Dutta Ray; Katharine Cecchini; Philip D. Zamore; Katey J. Rayner; Yves L. Marcel; Jennifer A. Philips; Kathryn J. Moore

doi:10.1038/ni.3434

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

Mireille Ouimet, Stefan Koster, Erik Sakowski, Bhama Ramkhelawon, Coen Van Solingen, Scott Oldebeken, Denuja Karunakaran, Cynthia Portal-Celhay, Frederick J. Sheedy, Tathagat Dutta Ray, Katharine Cecchini, Philip D. Zamore, Katey J. Rayner, Yves L. Marcel, Jennifer A. Philips, Kathryn J. Moore

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297 Scopus citations

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.

Original language	English
Pages (from-to)	677-686
Number of pages	10
Journal	Nature immunology
Volume	17
Issue number	6
DOIs	https://doi.org/10.1038/ni.3434
State	Published - May 19 2016

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Ouimet, M., Koster, S., Sakowski, E., Ramkhelawon, B., Van Solingen, C., Oldebeken, S., Karunakaran, D., Portal-Celhay, C., Sheedy, F. J., Ray, T. D., Cecchini, K., Zamore, P. D., Rayner, K. J., Marcel, Y. L., Philips, J. A., & Moore, K. J. (2016). Mycobacterium tuberculosis induces the MIR-33 locus to reprogram autophagy and host lipid metabolism. Nature immunology, 17(6), 677-686. https://doi.org/10.1038/ni.3434

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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.",

author = "Mireille Ouimet and Stefan Koster and Erik Sakowski and Bhama Ramkhelawon and {Van Solingen}, Coen and Scott Oldebeken and Denuja Karunakaran and Cynthia Portal-Celhay and Sheedy, {Frederick J.} and Ray, {Tathagat Dutta} and Katharine Cecchini and Zamore, {Philip D.} and Rayner, {Katey J.} and Marcel, {Yves L.} and Philips, {Jennifer A.} and Moore, {Kathryn J.}",

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year = "2016",

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doi = "10.1038/ni.3434",

language = "English",

volume = "17",

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Ouimet, M, Koster, S, Sakowski, E, Ramkhelawon, B, Van Solingen, C, Oldebeken, S, Karunakaran, D, Portal-Celhay, C, Sheedy, FJ, Ray, TD, Cecchini, K, Zamore, PD, Rayner, KJ, Marcel, YL, Philips, JA & Moore, KJ 2016, 'Mycobacterium tuberculosis induces the MIR-33 locus to reprogram autophagy and host lipid metabolism', Nature immunology, vol. 17, no. 6, pp. 677-686. https://doi.org/10.1038/ni.3434

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AU - Ouimet, Mireille

AU - Koster, Stefan

AU - Sakowski, Erik

AU - Ramkhelawon, Bhama

AU - Van Solingen, Coen

AU - Oldebeken, Scott

AU - Karunakaran, Denuja

AU - Portal-Celhay, Cynthia

AU - Sheedy, Frederick J.

AU - Ray, Tathagat Dutta

AU - Cecchini, Katharine

AU - Zamore, Philip D.

AU - Rayner, Katey J.

AU - Marcel, Yves L.

AU - Philips, Jennifer A.

AU - Moore, Kathryn J.

PY - 2016/5/19

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AB - 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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Mycobacterium tuberculosis induces the MIR-33 locus to reprogram autophagy and host lipid metabolism

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