title: Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling.
abstract: In human monocytes, Toll-like receptor (TLR) 2/1 activation leads to vitamin D3-dependent antimycobacterial activities, but the molecular mechanisms by which TLR2/1 stimulation induces antimicrobial activities against mycobacteria remain unclear. Here we show that TLR2/1/CD14 stimulation by mycobacterial lipoprotein LpqH can robustly activate antibacterial autophagy through vitamin D receptor signalling activation and cathelicidin induction. We found that CCAAT/enhancer-binding protein (C/EBP)-β-dependent induction of 25-hydroxycholecalciferol-1α-hydroxylase (Cyp27b1) hydroxylase was critical for LpqH-induced cathelicidin expression and autophagy. In addition, increases in intracellular calcium following AMP-activated protein kinase (AMPK) activation played a crucial role in LpqH-induced autophagy. Moreover, AMPK-dependent p38 mitogen-activated protein kinase (MAPK) activation was required for LpqH-induced Cyp27b1 expression and autophagy activation. Collectively, these data suggest that TLR2/1/CD14-Ca(2+) -AMPK-p38 MAPK pathways contribute to C/EBP-β-dependent expression of Cyp27b1 and cathelicidin, which played an essential role in LpqH-induced autophagy. Furthermore, these results establish a previously uncharacterized signalling pathway of antimycobacterial host defence through a functional link of TLR2/1/CD14-dependent sensing to the induction of autophagy.
authors.affiliation: Department of Microbiology, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: Dong-Min
authors.initials: DM
authors.lastname: Shin
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Yuk
authors.forename: Hye-Mi
authors.initials: HM
authors.lastname: Lee
authors.forename: Sang-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Ji Woong
authors.initials: JW
authors.lastname: Son
authors.forename: Clifford V
authors.initials: CV
authors.lastname: Harding
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002118:Calcium; D002478:Cells, Cultured; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000382:microbiology / Q000502:physiology*; D009169:Mycobacterium tuberculosis; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D022782:CCAAT-Enhancer-Binding Protein-beta; D018950:Lipopolysaccharide Receptors; D008074:Lipoproteins; D018167:Receptors, Calcitriol; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D014807:Vitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D002118:Calcium; D054804:Cathelicidins