MicroRNA 17-5p regulates autophagy inMycobacterium tuberculosis-infected macrophages by targeting Mcl-1 and STAT3

• DOI: 10.1111/cmi.12540
• Publication Date: 2015-10-29T21:28:36Z
• Authors: Ranjeet Kumar; Sanjaya Kumar Sahu; Manish Kumar; Kuladip Jana; Pushpa Gupta; Umesh D. Gupta; Manikuntala Kundu; Joyoti Basu
• Keywords: STAT3 Transcription Factor; 0301 basic medicine; Macrophages; Mycobacterium tuberculosis; 3. Good health; Mice; MicroRNAs; Protein Kinase C-delta; 03 medical and health sciences; HEK293 Cells; RAW 264.7 Cells; Autophagy; Animals; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Tuberculosis; Beclin-1; Signal Transduction

Autophagy plays a crucial role in the control of bacterial burden during Mycobacterium tuberculosis infection. MicroRNAs (miRNAs) are small non-coding RNAs that regulate immune signalling and inflammation in response to challenge by pathogens. Appreciating the potential of host-directed therapies designed to control autophagy during mycobacterial infection, we focused on the role of miRNAs in regulating M. tuberculosis-induced autophagy in macrophages. Here, we demonstrate that M. tuberculosis infection leads to downregulation of miR-17 and concomitant upregulation of its targets Mcl-1 and STAT3, a transcriptional activator of Mcl-1. Forced expression of miR-17 reduces expression of Mcl-1 and STAT3 and also the interaction between Mcl-1 and Beclin-1. This is directly linked to enhanced autophagy, because Mcl-1 overexpression attenuates the effects of miR-17. At the same time, transfection with a kinase-inactive mutant of protein kinase C δ (PKCδ) (an activator of STAT3) augments M. tuberculosis-induced autophagy, and miR-17 overexpression diminishes phosphorylation of PKCδ, suggesting that an miR-17/PKC δ/STAT3 axis regulates autophagy during M. tuberculosis infection.