<i>MIR144</i>* inhibits antimicrobial responses against <i>Mycobacterium tuberculosis</i> in human monocytes and macrophages by targeting the autophagy protein DRAM2
Creators: name: Kim, Jin Kyung
name: Lee, Hye-Mi
name: Park, Ki-Sun
name: Shin, Dong-Min
name: Kim, Tae Sung
name: Kim, Yi Sak
name: Suh, Hyun-Woo
name: Kim, Soo Yeon
name: Kim, In Soo
name: Kim, Jin-Man
name: Ji-Woong Son
name: Sohn, Kyung Mok
name: Jung, Sung Soo
name: Chaeuk Chung
name: Sang-Bae Han
name: Chul-Su Yang
name: Eun-Kyeong Jo
Publisher: name: Taylor & Francis
Year: 2016
Subjects: subject: Biochemistry
subject: Microbiology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Cell Biology
subject: Molecular Biology
subject: Physiology
subject: Pharmacology
subject: 59999 Environmental Sciences not elsewhere classified
subject: FOS: Earth and related environmental sciences
subject: FOS: Earth and related environmental sciences
subject: Science Policy
subject: Sociology
subject: FOS: Sociology
subject: FOS: Sociology
subject: Immunology
subject: FOS: Clinical medicine
subject: FOS: Clinical medicine
subject: Developmental Biology
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: FOS: Health sciences

description: Autophagy is an important antimicrobial effector process that defends against <i>Mycobacterium tuberculosis</i> (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 <i>MIR144*/hsa-miR-144-5p</i>, 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 <i>MIR144</i>* decreased <i>DRAM2</i> expression and formation of autophagosomes in human monocytes, whereas inhibition of <i>MIR144</i>* had the opposite effect. Moreover, the levels of <i>MIR144</i>* were elevated, whereas <i>DRAM2</i> levels were reduced, in human peripheral blood cells and tissues in TB patients, indicating the clinical significance of <i>MIR144</i>* and <i>DRAM2</i> 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, <i>MIR144</i>* and DRAM2 were critically involved in phagosomal maturation and enhanced antimicrobial effects against Mtb. Our findings identify a previously unrecognized role of human <i>MIR144</i>* 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.