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Autophagy, Volume 10, Issue 5, 2014 | DOI:10.4161/auto.28072 The AMPK-PPARGC1A pathway is required for antimicrobial host defense through activation of autophagy

Abstract

Chul-Su Yang,^1,2^,†Jwa-Jin Kim,^1,2,† Hye-Mi Lee,^1,2 Hyo Sun Jin,^1,2 Sang-Hee Lee,⁶ Ji-Hoon Park,^2,3Soung Jung Kim,⁴ Jin-Man Kim,^2,5Yong-Mahn Han,⁷ Myung-Shik Lee,⁸ Gi Ryang Kweon,^2,3Minho Shong,⁴and Eun-Kyeong Jo^1,2,*

¹Department of Microbiology; Chungnam National University School of Medicine; Daejeon, Korea; ²Infection Signaling Network Research Center; Chungnam National University School of Medicine; Daejeon, Korea; ³Department of Biochemistry; Chungnam National University School of Medicine; Daejeon, Korea; ⁴Department of Internal Medicine and Research Center for Endocrine and Metabolic Diseases; Chungnam National University School of Medicine; Daejeon, Korea; ⁵Department of Pathology; Chungnam National University School of Medicine; Daejeon, Korea; ⁶BioMedical Research Center; Korea Advanced Institute of Science and Technology; Daejeon, Korea; ⁷Department of Biological Sciences and Center for Stem Cell Differentiation; Korea Advanced Institute of Science and Technology; Daejeon, Korea; ⁸Department of Medicine; Samsung Medical Center; Sungkyunkwan University School of Medicine; Seoul, Korea

^†These authors contributed equally to this work.

^*Corresponding author

AMP-activated protein kinase (AMPK) is a crucial energy sensor and plays a key role in integration of cellular functions to maintain homeostasis. Despite this, it is largely unknown whether targeting the AMPK pathway can be used as a therapeutic strategy for infectious diseases. Herein, we show that AMPK activation robustly induces antibacterial autophagy, which contributes to antimicrobial defense against Mycobacterium tuberculosis (Mtb). AMPK activation led to inhibition of Mtb-induced phosphorylation of the mechanistic target of rapamycin (MTOR) in macrophages. In addition, AMPK activation increased the genes involved in oxidative phosphorylation, mitochondrial ATP production and biogenesis in Mtb-infected macrophages. Notably, peroxisome proliferator-activated receptor-gamma, coactivator 1α (PPARGC1A) was required for AMPK-mediated antimicrobial activity, as well as enhancement of mitochondrial function and biogenesis, in macrophages. Further, the AMPK-PPARGC1A pathway was involved in the upregulation of multiple autophagy-related genes via CCAAT/enhancer binding protein (C/EBP), β (CEBPB). PPARGC1A knockdown inhibited the AMPK-mediated induction of autophagy and impaired the fusion of phagosomes with MAP1LC3B (LC3B) autophagosomes in Mtb-infected macrophages. The link between autophagy, mitochondrial function, and antimicrobial activity was further demonstrated by studying LysMCre-mediated knockout of atg7, demonstrating mitochondrial ultrastructural defects and dysfunction, as well as blockade of antimicrobial activity against mycobacteria. Collectively, our results identify the AMPK-PPARGC1A axis as contributing to autophagy activation leading to an antimicrobial response, as a novel host defense mechanism.

Keywords: AICAR, AMP-activated protein kinase, autophagy, MTOR, Mycobacterium tuberculosis, PPARGC1A

논문정보

TOP52014년 선정

형식Research article
게재일2014년 01월 (BRIC 등록일 2014-02-28)
연구진국내 연구진
분야 의약학 > 면역의학

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