Abstract
Ubiquitin-mediated targeting of intracellular bacteria to the autophagy pathway is a key innate defence mechanism against invading microbes, including the important human pathogen Mycobacterium tuberculosis. However, the ubiquitin ligases responsible for catalysing ubiquitin chains that surround intracellular bacteria are poorly understood. The parkin protein is a ubiquitin ligase with a well-established role in mitophagy, and mutations in the parkin gene (PARK2) lead to increased susceptibility to Parkinson's disease. Surprisingly, genetic polymorphisms in the PARK2 regulatory region are also associated with increased susceptibility to intracellular bacterial pathogens in humans, including Mycobacterium leprae and Salmonella enterica serovar Typhi, but the function of parkin in immunity has remained unexplored. Here we show that parkin has a role in ubiquitin-mediated autophagy of M. tuberculosis. Both parkin-deficient mice and flies are sensitive to various intracellular bacterial infections, indicating parkin has a conserved role in metazoan innate defence. Moreover, our work reveals an unexpected functional link between mitophagy and infectious disease.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Autophagy / immunology
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Bone Marrow Cells / microbiology
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Drosophila melanogaster / genetics
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Drosophila melanogaster / immunology*
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Drosophila melanogaster / metabolism
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Drosophila melanogaster / microbiology*
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Female
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Immunity, Innate / immunology*
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Lysine / metabolism
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Macrophages / microbiology
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Male
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Mice
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Mice, Inbred C57BL
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Mitochondria / metabolism
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Mitochondria / pathology
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Mitophagy
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Models, Immunological
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Mycobacterium marinum / immunology*
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Mycobacterium tuberculosis / growth & development
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Mycobacterium tuberculosis / immunology*
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Mycobacterium tuberculosis / metabolism
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Polyubiquitin / chemistry
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Polyubiquitin / metabolism
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Salmonella typhimurium / immunology*
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Symbiosis / immunology
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Tuberculosis / enzymology
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Tuberculosis / immunology
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Tuberculosis / microbiology
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Tuberculosis / pathology
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Ubiquitin / analysis
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Ubiquitin / chemistry
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases / chemistry
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Ubiquitin-Protein Ligases / deficiency
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Ubiquitin-Protein Ligases / immunology*
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Ubiquitin-Protein Ligases / metabolism
Substances
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Ubiquitin
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Polyubiquitin
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Ubiquitin-Protein Ligases
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parkin protein
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Lysine