title: MIR144* inhibits antimicrobial responses against Mycobacterium tuberculosis in human monocytes and macrophages by targeting the autophagy protein DRAM2.
abstract: Autophagy is an important antimicrobial effector process that defends against Mycobacterium tuberculosis (Mtb), the human pathogen causing tuberculosis (TB). MicroRNAs (miRNAs), endogenous noncoding RNAs, are involved in various biological functions and act as post-transcriptional regulators to target mRNAs. The process by which miRNAs affect antibacterial autophagy and host defense mechanisms against Mtb infections in human monocytes and macrophages is largely uncharacterized. In this study, we show that Mtb significantly induces the expression of MIR144*/hsa-miR-144-5p, which targets the 3'-untranslated region of DRAM2 (DNA damage regulated autophagy modulator 2) in human monocytes and macrophages. Mtb infection downregulated, whereas the autophagy activators upregulated, DRAM2 expression in human monocytes and macrophages by activating AMP-activated protein kinase. In addition, overexpression of MIR144* decreased DRAM2 expression and formation of autophagosomes in human monocytes, whereas inhibition of MIR144* had the opposite effect. Moreover, the levels of MIR144* were elevated, whereas DRAM2 levels were reduced, in human peripheral blood cells and tissues in TB patients, indicating the clinical significance of MIR144* and DRAM2 in human TB. Notably, DRAM2 interacted with BECN1 and UVRAG, essential components of the autophagic machinery, leading to displacement of RUBCN from the BECN1 complex and enhancement of Ptdlns3K activity. Furthermore, MIR144* and DRAM2 were critically involved in phagosomal maturation and enhanced antimicrobial effects against Mtb. Our findings identify a previously unrecognized role of human MIR144* in the inhibition of antibacterial autophagy and the innate host immune response to Mtb. Additionally, these data reveal that DRAM2 is a key coordinator of autophagy activation that enhances antimicrobial activity against Mtb.
authors.affiliation: a Department of Microbiology , Chungnam National University School of Medicine , Daejeon , Korea.|b Department of Medical Science , Chungnam National University School of Medicine , Daejeon , Korea.
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Kim
authors.affiliation: a Department of Microbiology , Chungnam National University School of Medicine , Daejeon , Korea.
authors.forename: Hye-Mi
authors.initials: HM
authors.lastname: Lee
authors.affiliation: c Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda , MD , USA.
authors.forename: Ki-Sun
authors.initials: KS
authors.lastname: Park
authors.affiliation: a Department of Microbiology , Chungnam National University School of Medicine , Daejeon , Korea.
authors.forename: Dong-Min
authors.initials: DM
authors.lastname: Shin
authors.affiliation: a Department of Microbiology , Chungnam National University School of Medicine , Daejeon , Korea.|b Department of Medical Science , Chungnam National University School of Medicine , Daejeon , Korea.
authors.forename: Tae Sung
authors.initials: TS
authors.lastname: Kim
authors.affiliation: a Department of Microbiology , Chungnam National University School of Medicine , Daejeon , Korea.|b Department of Medical Science , Chungnam National University School of Medicine , Daejeon , Korea.
authors.forename: Yi Sak
authors.initials: YS
authors.lastname: Kim
authors.affiliation: a Department of Microbiology , Chungnam National University School of Medicine , Daejeon , Korea.|b Department of Medical Science , Chungnam National University School of Medicine , Daejeon , Korea.
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Suh
authors.affiliation: a Department of Microbiology , Chungnam National University School of Medicine , Daejeon , Korea.|b Department of Medical Science , Chungnam National University School of Medicine , Daejeon , Korea.
authors.forename: Soo Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: a Department of Microbiology , Chungnam National University School of Medicine , Daejeon , Korea.
authors.forename: In Soo
authors.initials: IS
authors.lastname: Kim
authors.affiliation: b Department of Medical Science , Chungnam National University School of Medicine , Daejeon , Korea.|d Department of Pathology , Chungnam National University School of Medicine , Daejeon , Korea.
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.affiliation: e Department of Internal Medicine , Konyang University , Daejeon , Korea.
authors.forename: Ji-Woong
authors.initials: JW
authors.lastname: Son
authors.affiliation: f Division of Infectious Diseases, Department of Internal Medicine , Chungnam National University School of Medicine , Daejeon , Korea.
authors.forename: Kyung Mok
authors.initials: KM
authors.lastname: Sohn
authors.affiliation: g Division of Pulmonary and Critical Care, Department of Internal Medicine , Chungnam National University School of Medicine , Daejeon , Korea.
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Jung
authors.affiliation: g Division of Pulmonary and Critical Care, Department of Internal Medicine , Chungnam National University School of Medicine , Daejeon , Korea.
authors.forename: Chaeuk
authors.initials: C
authors.lastname: Chung
authors.affiliation: h College of Pharmacy, Chungbuk National University , Cheongju , Korea.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: i Department of Molecular and Life Science , Hanyang University , Ansan , Korea.
authors.forename: Chul-Su
authors.initials: CS
authors.lastname: Yang
authors.affiliation: a Department of Microbiology , Chungnam National University School of Medicine , Daejeon , Korea.|b Department of Medical Science , Chungnam National University School of Medicine , Daejeon , Korea.
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D000071183:Autophagy-Related Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D000071186:Beclin-1 / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D014376:Tuberculosis / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; C544299:DRAM2 protein, human; C554293:MIRN144 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases
keywords: AMPK; DRAM2; MIR144*; Mycobacterium tuberculosis; tuberculosis