MicroRNA-125a Inhibits Autophagy Activation and Antimicrobial Responses during Mycobacterial Infection.
MicroRNAs (miRNAs) are small noncoding nucleotides that play critical roles in the regulation of diverse biological functions, including the response of host immune cells. Autophagy plays a key role in activating the antimicrobial host defense against Mycobacterium tuberculosis. Although the pathways associated with autophagy must be tightly regulated at a posttranscriptional level, the contribution of miRNAs and whether they specifically influence the activation of macrophage autophagy during M. tuberculosis infection are largely unknown. In this study, we demonstrate that M. tuberculosis infection of macrophages leads to increased expression of miRNA-125a-3p (miR-125a), which targets UV radiation resistance-associated gene (UVRAG), to inhibit autophagy activation and antimicrobial responses to M. tuberculosis. Forced expression of miR-125a significantly blocked M. tuberculosis-induced activation of autophagy and phagosomal maturation in macrophages, and inhibitors of miR-125a counteracted these effects. Both TLR2 and MyD88 were required for biogenesis of miR-125a during M. tuberculosis infection. Notably, activation of the AMP-activated protein kinase significantly inhibited the expression of miR-125a in M. tuberculosis-infected macrophages. Moreover, either overexpression of miR-125a or silencing of UVRAG significantly attenuated the antimicrobial effects of macrophages against M. tuberculosis. Taken together, these data indicate that miR-125a regulates the innate host defense by inhibiting the activation of autophagy and antimicrobial effects against M. tuberculosis through targeting UVRAG.
Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea;
Jin Kyung
JK
Kim
Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Department of Infection Biology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea;
Jae-Min
JM
Yuk
Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea;
Soo Yeon
SY
Kim
Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea;
Tae Sung
TS
Kim
Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea;
Hyo Sun
HS
Jin
Department of Molecular and Life Science, College of Science and Technology, Hanyang University, Ansan 426-791, South Korea; and.
Chul-Su
CS
Yang
Department of Microbiology, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon 301-747, South Korea; Research Institute for Medical Sciences, Chungnam National University School of Medicine, Daejeon 301-747, South Korea hayoungj@cnu.ac.kr.
Eun-Kyeong
EK
Jo
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002460:Cell Line; D005786:Gene Expression Regulation; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051195:Toll-Like Receptor 2; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D025521:Tumor Suppressor Proteins; C512859:UVRAG protein, mouse; D055372:AMP-Activated Protein Kinases