title: MicroRNA 17-5p regulates autophagy in Mycobacterium tuberculosis-infected macrophages by targeting Mcl-1 and STAT3.
abstract: 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.
authors.affiliation: Department of Chemistry, Bose Institute, Kolkata, 700009, India.
authors.forename: Ranjeet
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, Bose Institute, Kolkata, 700009, India.
authors.forename: Sanjaya Kumar
authors.initials: SK
authors.lastname: Sahu
authors.affiliation: Department of Chemistry, Bose Institute, Kolkata, 700009, India.
authors.forename: Manish
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, 700054, India.
authors.forename: Kuladip
authors.initials: K
authors.lastname: Jana
authors.affiliation: National Jalma Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, 282006, India.
authors.forename: Pushpa
authors.initials: P
authors.lastname: Gupta
authors.affiliation: National Jalma Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, 282006, India.
authors.forename: Umesh D
authors.initials: UD
authors.lastname: Gupta
authors.affiliation: Department of Chemistry, Bose Institute, Kolkata, 700009, India.
authors.forename: Manikuntala
authors.initials: M
authors.lastname: Kundu
authors.affiliation: Department of Chemistry, Bose Institute, Kolkata, 700009, India.
authors.forename: Joyoti
authors.initials: J
authors.lastname: Basu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071186:Beclin-1 / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000472:pathogenicity; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics*; D051745:Protein Kinase C-delta / Q000235:genetics; D000067996:RAW 264.7 Cells; D050796:STAT3 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014376:Tuberculosis / Q000235:genetics* / Q000382:microbiology
chemical_list: D000071186:Beclin-1; C579095:MCL1 protein, human; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D050796:STAT3 Transcription Factor; D051745:Protein Kinase C-delta