The AMPK-PPARGC1A pathway is required for antimicrobial host defense through activation of autophagy
| Autor: | Soung Jung Kim, Minho Shong, Myung-Shik Lee, Ji-Hoon Park, Chul-Su Yang, Yong-Mahn Han, Gi Ryang Kweon, Jin-Man Kim, Eun-Kyeong Jo, Sang-Hee Lee, Hyo Sun Jin, J.W. Kim, Hye-Mi Lee |
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| Rok vydání: | 2014 |
| Předmět: |
Mice
Transgenic AMP-Activated Protein Kinases Mycobacterium Mice AMP-activated protein kinase Enhancer binding Autophagy Animals Humans Molecular Biology Mechanistic target of rapamycin Cells Cultured PI3K/AKT/mTOR pathway biology AMPK Cell Biology Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Basic Research Paper Immunity Innate Cell biology Mice Inbred C57BL Drosophila melanogaster Mitochondrial biogenesis Host-Pathogen Interactions biology.protein MAP1LC3B Signal Transduction Transcription Factors |
| Zdroj: | Autophagy. 10:785-802 |
| ISSN: | 1554-8635 1554-8627 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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