RESUMO
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.
Assuntos
Drosophila melanogaster/imunologia , Drosophila melanogaster/microbiologia , Imunidade Inata/imunologia , Mycobacterium marinum/imunologia , Mycobacterium tuberculosis/imunologia , Salmonella typhimurium/imunologia , Ubiquitina-Proteína Ligases/imunologia , Animais , Autofagia/imunologia , Células da Medula Óssea/microbiologia , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Feminino , Lisina/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitofagia , Modelos Imunológicos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/metabolismo , Poliubiquitina/química , Poliubiquitina/metabolismo , Simbiose/imunologia , Tuberculose/enzimologia , Tuberculose/imunologia , Tuberculose/microbiologia , Tuberculose/patologia , Ubiquitina/análise , Ubiquitina/química , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Leprosy is a chronic infectious disease caused by Mycobacterium leprae that affects an estimated 700,000 new individuals each year. A strong contribution of host genetics to susceptibility to leprosy has long been suggested to account for the considerable variability observed between individuals exposed to M. leprae. As there is no relevant animal model for human leprosy, forward genetics is the main strategy used to identify the genes and, consequently, the immunological pathways involved in protective immunity to M. leprae. With respect to genome-wide screens, a major breakthrough has been reported this year; variants in the regulatory region shared by PARK2 and PACRG have been identified as being common risk factors for leprosy.