title: The AMPK-PPARGC1A pathway is required for antimicrobial host defense through activation of autophagy.
abstract: 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.
authors.affiliation: Department of Microbiology; Chungnam National University School of Medicine; Daejeon, Korea; Infection Signaling Network Research Center; Chungnam National University School of Medicine; Daejeon, Korea.
authors.forename: Chul-Su
authors.initials: CS
authors.lastname: Yang
authors.affiliation: Department of Microbiology; Chungnam National University School of Medicine; Daejeon, Korea; Infection Signaling Network Research Center; Chungnam National University School of Medicine; Daejeon, Korea.
authors.forename: Jwa-Jin
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Microbiology; Chungnam National University School of Medicine; Daejeon, Korea; Infection Signaling Network Research Center; Chungnam National University School of Medicine; Daejeon, Korea.
authors.forename: Hye-Mi
authors.initials: HM
authors.lastname: Lee
authors.affiliation: Department of Microbiology; Chungnam National University School of Medicine; Daejeon, Korea; Infection Signaling Network Research Center; Chungnam National University School of Medicine; Daejeon, Korea.
authors.forename: Hyo Sun
authors.initials: HS
authors.lastname: Jin
authors.affiliation: BioMedical Research Center; Korea Advanced Institute of Science and Technology; Daejeon, Korea.
authors.forename: Sang-Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Infection Signaling Network Research Center; Chungnam National University School of Medicine; Daejeon, Korea; Department of Biochemistry; Chungnam National University School of Medicine; Daejeon, Korea.
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Internal Medicine and Research Center for Endocrine and Metabolic Diseases; Chungnam National University School of Medicine; Daejeon, Korea.
authors.forename: Soung Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Infection Signaling Network Research Center; Chungnam National University School of Medicine; Daejeon, Korea; Department of Pathology; Chungnam National University School of Medicine; Daejeon, Korea.
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences and Center for Stem Cell Differentiation; Korea Advanced Institute of Science and Technology; Daejeon, Korea.
authors.forename: Yong-Mahn
authors.initials: YM
authors.lastname: Han
authors.affiliation: Department of Medicine; Samsung Medical Center; Sungkyunkwan University School of Medicine; Seoul, Korea.
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Infection Signaling Network Research Center; Chungnam National University School of Medicine; Daejeon, Korea; Department of Biochemistry; Chungnam National University School of Medicine; Daejeon, Korea.
authors.forename: Gi Ryang
authors.initials: GR
authors.lastname: Kweon
authors.affiliation: Department of Internal Medicine and Research Center for Endocrine and Metabolic Diseases; Chungnam National University School of Medicine; Daejeon, Korea.
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.affiliation: Department of Microbiology; Chungnam National University School of Medicine; Daejeon, Korea; Infection Signaling Network Research Center; Chungnam National University School of Medicine; Daejeon, Korea.
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002478:Cells, Cultured; D004331:Drosophila melanogaster; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009161:Mycobacterium / Q000276:immunology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014157:Transcription Factors / Q000502:physiology*
chemical_list: C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D055372:AMP-Activated Protein Kinases
keywords: AICAR; AMP-activated protein kinase; MTOR; Mycobacterium tuberculosis; PPARGC1A; autophagy