한빛사논문
- 조회1,408
Abstract
Jin Kyung Kima,b,†, Hye-Mi Leea,†, Ki-Sun Parkc, Dong-Min Shina, Tae Sung Kima,b, Yi Sak Kima,b, Hyun-Woo Suha,b, Soo Yeon Kima,b, In Soo Kima, Jin-Man Kimb,d, Ji-Woong Sone, Kyung Mok Sohnf, Sung Soo Jungg, Chaeuk Chungg, Sang-Bae Hanh, Chul-Su Yangi,‡, and Eun-Kyeong Joa,b,‡
aDepartment of Microbiology, Chungnam National University School of Medicine, Daejeon, Korea; bDepartment of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea; cProgram in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA; dDepartment of Pathology, Chungnam National University School of Medicine, Daejeon, Korea; eDepartment of Internal Medicine, Konyang University, Daejeon, Korea; fDivision of Infectious Diseases, Department ofInternal Medicine, Chungnam National University School of Medicine, Daejeon, Korea; gDivision of Pulmonary and Critical Care, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea; hCollege of Pharmacy, Chungbuk National University, Cheongju, Korea; iDepartment of Molecular and Life Science, Hanyang University, Ansan, Korea
†These authors contributed equally to this work.
‡Correspondence : Chul-Su Yang, Eun-Kyeong Jo
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.
Key words: AMPK, DRAM2, MIR144*, Mycobacterium tuberculosis, tuberculosis, Disclaimer
논문정보
- Research article
- 2016년 10월 (BRIC 등록일 2016-11-07)
- 국내(교신)+국외 연구진
- 의약학 > 면역의학
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