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  • Title: miR-18a promotes Mycobacterial survival in macrophages via inhibiting autophagy by down-regulation of ATM.
    Author: Yuan Q, Chen H, Yang Y, Fu Y, Yi Z.
    Journal: J Cell Mol Med; 2020 Jan; 24(2):2004-2012. PubMed ID: 31845528.
    Abstract:
    Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of leading causes of global deaths. This study aimed to explore the role of miR-18a in RAW264.7 cells response to Mtb infection. Exosomes derived from Mtb-infected cells were isolated and further validated by size, transmission electron microscopy and Western blot. RT-PCR was utilized to measure miR-18a expression. Cell viability and ultrastructure were examined by CFU counting, CCK-8 and electron microscope, respectively. Potential target genes of miR-18a were predicted with bioinformatics and further confirmed using RT-PCR, Western blot and laser confocal microscope analysis, respectively. LC3, AMPK and mTOR were measured using Western blot. We found that miR-18a was induced both in Mtb-infected RAW264.7 cells and its derived exosomes compared with the controls. In addition, up-regulation of miR-18a promoted intracellular Mtb survival, attenuated cell viability and reduced LC3-II level, while its down-regulation had the opposite effect. miR-18a overexpression suppressed level of ATM, one possible target of miR-18a, while its underexpression enhanced ATM. We also found that inhibition of ATM induced LC3-II decrease in Mtb-infected cells and could reverse the increase of LC3-II caused by inhibition of miR-18a. Moreover, down-regulation of miR-18a increased p-AMPK level while reduction of ATM could reverse the change. Taken together, our results suggest that miR-18a is up-regulated in macrophages response to Mtb infection, and it promotes intracellular Mtb survival through repressing autophagic process by down-regulation of ATM pathway. This provides new thought for TB pathogenesis, diagnosis and treatment.
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