title: The DNA damage-regulated autophagy modulator DRAM1 links mycobacterial recognition via TLR-MYD88 to autophagic defense [corrected].
abstract: Autophagy is an important defense mechanism against mycobacteria, the causative agents of tuberculosis. The molecular mechanisms that link mycobacterial recognition to autophagy remain unclear. Our analysis in zebrafish and human macrophage models of mycobacterial infection reveals that the DNA damage-regulated autophagy modulator DRAM1 functions downstream of pathogen recognition by the Toll-like receptor (TLR)/interleukin-1 receptor (IL1R)-MYD88-NF-κB innate immune sensing pathway to activate selective autophagy. Mycobacterial infection of human macrophages and zebrafish embryos induced DRAM1 expression in a MYD88 and NF-κB-dependent manner. DRAM1 knockdown increased mycobacterial infection, whereas overexpression lowered infection by hyperactivating autophagy. DRAM1-mediated selective autophagic defenses require the cytosolic DNA sensor STING and the selective autophagy receptor p62/SQSTM1. Contrary to its known role in autophagy-mediated cell death and cancer, this DRAM1 function is p53 independent. We propose that DRAM1 mediates autophagic defense against a broader range of intracellular pathogens, since DRAM1 expression was also induced by the common bacterial endotoxin lipopolysaccharide.
authors.affiliation: Institute of Biology, Leiden University, 2333 CC Leiden, the Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: van der Vaart
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Korbee
authors.affiliation: Institute of Biology, Leiden University, 2333 CC Leiden, the Netherlands.
authors.forename: Gerda E M
authors.initials: GE
authors.lastname: Lamers
authors.affiliation: Institute of Biology, Leiden University, 2333 CC Leiden, the Netherlands.
authors.forename: Anouk C
authors.initials: AC
authors.lastname: Tengeler
authors.affiliation: Institute of Biology, Leiden University, 2333 CC Leiden, the Netherlands.
authors.forename: Rohola
authors.initials: R
authors.lastname: Hosseini
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
authors.forename: Mariëlle C
authors.initials: MC
authors.lastname: Haks
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.affiliation: Institute of Biology, Leiden University, 2333 CC Leiden, the Netherlands.
authors.forename: Herman P
authors.initials: HP
authors.lastname: Spaink
authors.affiliation: Institute of Biology, Leiden University, 2333 CC Leiden, the Netherlands. Electronic address: a.h.meijer@biology.leidenuniv.nl.
authors.forename: Annemarie H
authors.initials: AH
authors.lastname: Meijer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000276:immunology; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000382:microbiology; D005786:Gene Expression Regulation; D016158:Genes, p53; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000382:microbiology* / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009161:Mycobacterium / Q000472:pathogenicity*; D009164:Mycobacterium Infections / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015027:Zebrafish / Q000196:embryology / Q000382:microbiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C512709:DRAM1 protein, human; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein