02427nas a2200505   4500000000100000008004100001260001600042653001200058653001400070653002200084653002800106653001100134653002100145653001100166653001600177653000900193653000900202653002300211653001700234653003000251653002600281653002600307653003100333653001800364653002700382653001400409653001700423653001400440653003000454100001800484700001200502700001300514700001500527700001200542700001000554700001700564700001500581700001400596700001100610245008000621300001000701490000800711520118800719022001401907       2013                            d  c2013 Sep 2610aAnimals10aAutophagy10aBone Marrow Cells10aDrosophila melanogaster10aFemale10aImmunity, Innate10aLysine10aMacrophages10aMale10aMice10aMice, Inbred C57BL10aMitochondria10aMitochondrial Degradation10aModels, Immunological10aMycobacterium marinum10aMycobacterium tuberculosis10aPolyubiquitin10aSalmonella typhimurium10aSymbiosis10aTuberculosis10aUbiquitin10aUbiquitin-Protein Ligases1 aManzanillo PS1 aAyres J1 aWatson R1 aCollins AC1 aSouza G1 aRae C1 aSchneider DS1 aNakamura K1 aShiloh MU1 aCox JS00aThe ubiquitin ligase parkin mediates resistance to intracellular pathogens.  a512-60 v5013 a<p>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. </p>  a1476-4687