title: The ubiquitin ligase parkin mediates resistance to intracellular pathogens.
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.
authors.affiliation: Department of Microbiology and Immunology Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Paolo S
authors.initials: PS
authors.lastname: Manzanillo
authors.forename: Janelle S
authors.initials: JS
authors.lastname: Ayres
authors.forename: Robert O
authors.initials: RO
authors.lastname: Watson
authors.forename: Angela C
authors.initials: AC
authors.lastname: Collins
authors.forename: Gianne
authors.initials: G
authors.lastname: Souza
authors.forename: Chris S
authors.initials: CS
authors.lastname: Rae
authors.forename: David S
authors.initials: DS
authors.lastname: Schneider
authors.forename: Ken
authors.initials: K
authors.lastname: Nakamura
authors.forename: Michael U
authors.initials: MU
authors.lastname: Shiloh
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Cox
mesh_terms: D000818:Animals; D001343:Autophagy / Q000276:immunology; D001854:Bone Marrow Cells / Q000382:microbiology; D004331:Drosophila melanogaster / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D005260:Female; D007113:Immunity, Innate / Q000276:immunology*; D008239:Lysine / Q000378:metabolism; D008264:Macrophages / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D063306:Mitophagy; D018448:Models, Immunological; D019910:Mycobacterium marinum / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology* / Q000378:metabolism; D025821:Polyubiquitin / Q000737:chemistry / Q000378:metabolism; D012486:Salmonella typhimurium / Q000276:immunology*; D013559:Symbiosis / Q000276:immunology; D014376:Tuberculosis / Q000201:enzymology / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D025801:Ubiquitin / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism
chemical_list: D025801:Ubiquitin; D025821:Polyubiquitin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D008239:Lysine