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

Research output: Contribution to journal › Article › Research › peer-review

299 Citations (Scopus)

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
Publication status	Published - Jun 2016
Externally published	Yes

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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

@article{164d68211909463ebf5c7783fea06e98,

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.}",

note = "Funding Information: We thank H. Virgin (Washington University School of Medicine) and D. MacDuff (Washington University School of Medicine) for Cgas-/- mice; K. Caldwell (New York University) for Atg16l1flox/flox mice; B. Norris for help with flow cytometry; C. O'Shaughnessy for help with mouse harvests; New York University Langone Medical Center Immune Monitoring Core for use of the XFe24 Extracellular Flux Analyzer (supported by the NYU-HHC CTSI grant UL1 TR000038 and the NYU Cancer Institute's Cancer Center Support grant P30CA016087). Supported by the US National Institutes of Health (R01 HL108182 and HL119047 to K.J.M.; R01 AI087682 and R21 AI105298 to J.A.P.), the American Heart Association (13POST14490016 to B.R., 14POST20180018 to C.v.S.), the NYU Physician-Scientist Training Program (C.P.-C.), the Potts Memorial Foundation (S.K.), Edward J. Mallinckrodt, Jr. Foundation (J.A.P.), Science Foundation Ireland (13/SIRG/2136 to F.J.S.), and the Canadian Institutes of Health Research (postdoctoral fellowship to M.O.; MOP130365 and MSH130157 to K.J.R.). Publisher Copyright: {\textcopyright} 2016 Nature America, Inc.",

year = "2016",

month = jun,

doi = "10.1038/ni.3434",

language = "English",

volume = "17",

pages = "677--686",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

number = "6",

}

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

TY - JOUR

T1 - Mycobacterium tuberculosis induces the MIR-33 locus to reprogram autophagy and host lipid metabolism

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.

N1 - Funding Information: We thank H. Virgin (Washington University School of Medicine) and D. MacDuff (Washington University School of Medicine) for Cgas-/- mice; K. Caldwell (New York University) for Atg16l1flox/flox mice; B. Norris for help with flow cytometry; C. O'Shaughnessy for help with mouse harvests; New York University Langone Medical Center Immune Monitoring Core for use of the XFe24 Extracellular Flux Analyzer (supported by the NYU-HHC CTSI grant UL1 TR000038 and the NYU Cancer Institute's Cancer Center Support grant P30CA016087). Supported by the US National Institutes of Health (R01 HL108182 and HL119047 to K.J.M.; R01 AI087682 and R21 AI105298 to J.A.P.), the American Heart Association (13POST14490016 to B.R., 14POST20180018 to C.v.S.), the NYU Physician-Scientist Training Program (C.P.-C.), the Potts Memorial Foundation (S.K.), Edward J. Mallinckrodt, Jr. Foundation (J.A.P.), Science Foundation Ireland (13/SIRG/2136 to F.J.S.), and the Canadian Institutes of Health Research (postdoctoral fellowship to M.O.; MOP130365 and MSH130157 to K.J.R.). Publisher Copyright: © 2016 Nature America, Inc.

PY - 2016/6

Y1 - 2016/6

N2 - 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.

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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U2 - 10.1038/ni.3434

DO - 10.1038/ni.3434

M3 - Article

C2 - 27089382

AN - SCOPUS:84964374656

SN - 1529-2908

VL - 17

SP - 677

EP - 686

JO - Nature Immunology

JF - Nature Immunology

IS - 6

ER -

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

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