MicroRNA-27a controls the intracellular survival of Mycobacterium tuberculosis by regulating calcium-associated autophagy

Feng Liu,Haohao Li,Peng Wang,Jianxia Chen,Hua Yang,Baoxue Ge,Xiaochen Huang,Jie Wang,Heping Xiao,Ruijuan Zheng,Haipeng Liu,Fei Wang,Wei Sha,Zhenling Cui,Lin Wang,Yilong Zhou,Zhonghua Liu

doi:10.1038/s41467-018-06836-4

Feng Liu, Haohao Li + Show 15 more

Open Access

https://doi.org/10.1038/s41467-018-06836-4

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Abstract

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) kills millions every year, and there is urgent need to develop novel anti-TB agents due to the fast-growing of drug-resistant TB. Although autophagy regulates the intracellular survival of Mtb, the role of calcium (Ca2+) signaling in modulating autophagy during Mtb infection remains largely unknown. Here, we show that microRNA miR-27a is abundantly expressed in active TB patients, Mtb-infected mice and macrophages. The target of miR-27a is the ER-located Ca2+ transporter CACNA2D3. Targeting of this transporter leads to the downregulation of Ca2+ signaling, thus inhibiting autophagosome formation and promoting the intracellular survival of Mtb. Mice lacking of miR-27a and mice treated with an antagomir to miR-27a are more resistant to Mtb infection. Our findings reveal a strategy for Mtb to increase intracellular survival by manipulating the Ca2+-associated autophagy, and may also support the development of host-directed anti-TB therapeutic approaches.

Highlights

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) kills millions every year, and there is urgent need to develop novel anti-TB agents due to the fast-growing of drug-resistant TB
We evaluated miRNA expression profiles from peripheral blood mononuclear cells (PBMCs) of the patients with active pulmonary TB, the lungs of Mtb strain H37Rv-infected C57/BL6 mice, and H37Rv-infected murine primary peritoneal macrophages
As miR-27a’s functional role in regulation of Mtb infection remains uncharacterized, we choose it for our further study

Summary

Introduction

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) kills millions every year, and there is urgent need to develop novel anti-TB agents due to the fast-growing of drug-resistant TB. Autophagy regulates the intracellular survival of Mtb, the role of calcium (Ca2+) signaling in modulating autophagy during Mtb infection remains largely unknown. The target of miR-27a is the ER-located Ca2+ transporter CACNA2D3 Targeting of this transporter leads to the downregulation of Ca2+ signaling, inhibiting autophagosome formation and promoting the intracellular survival of Mtb. Mice lacking of miR-27a and mice treated with an antagomir to miR-27a are more resistant to Mtb infection. AMPK-phosphorylated ULK1 forms a complex with FIP200 (200 kDa focal adhesion kinase family-interacting protein) and ATG13 to induce autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase[10]. Recent work demonstrated that autophagy played an important role in the containment of intracellular Mtb by targeting Mtb for lysosome degradation, bypassing Mtb-mediated blockade of phagosome maturation[13]. Our understanding of the role of miRNAs in modulating autophagic signaling pathways during Mtb infection and their clinical relevance is still limited

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