MicroRNA 17-5p regulates autophagy inMycobacterium 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 noncoding 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. tuberculosisinduced autophagy, and miR-17 overexpression diminishes phosphorylation of PKCδ, suggesting that an miR-17/PKC δ/STAT3 axis regulates autophagy during M. tuberculosis infection.

MicroRNA-17 Suppresses TNF-α Signaling by Interfering with TRAF2 and cIAP2 Association in Rheumatoid Arthritis Synovial Fibroblasts

“…6G). MiR-17 has been shown to target STAT3 3’UTR and regulate STAT3 expression, thereby, leading to a loss of suppressive function in myeloid-derived suppressive cells (35, 36). Consistent with the previous findings, an overexpression of miR-17 reduced the nuclear translocation of p-STAT3 in TNF-α-stimulated RASFs (Fig.…”

“…We hypothesize that miR-17 may regulate TNF-α signaling at multiple steps in RA and its influence on TRAF2 and cIAP2 may be the earliest and most prominent in TNF-α signaling pathway. In addition, recent studies have shown that miR-17 targets STAT3 3’UTR to regulate its expression in myeloid-derived suppressive cells and in other cell types (35, 36), suggesting STAT3 regulation may be a downstream direct effect of miR-17 through 3’UTR binding.…”

Autophagy: A double-edged sword in intervertebral disk degeneration

“…As a class of small noncoding RNA molecules that can suppress gene expression by targeting mRNAs for translational repression and/or cleavage, miRNAs have been shown to be involved in disc degeneration [15]. It has been reported that miRNAs are able to regulate autophagy in multiple types of cells, such as colorectal cancer cells [158], gastric cancer cells [159], macrophages [160], and tubular epithelial cells [161].…”

Immune Evasion Strategies of Pathogens in Macrophages: the Potential for Limiting Pathogen Transmission

“…However, the impact of autophagy on M. tuberculosis is complicated. It has been reported that enhanced autophagy is capable of promoting M. tuberculosis survival (Kumar et al, 2015), whereas nordihydroguaiaretic acid (NDGA) and α-mangostininduced autophagy can inhibit the replication of M. tuberculosis in infected macrophages derived from the human THP-1 cell line (Guzmán-Beltrán et al, 2015). Furthermore, the impact on apoptosis and autophagy exerted by PRRSV might be different in vivo and in vitro and change with various target cells.…”