PARKIN ubiquitin ligase mediates resistance to intracellular pathogens

Ubiquitin-mediated targeting of intracellular bacteria to the autophagy pathway is a key innate defense mechanism against invading microbes, including the important human pathogen Mycobacterium tuberculosis. However, the ubiquitin ligases responsible for catalyzing ubiquitin chains that surround intracellular bacteria are poorly understood. PARKIN 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 typhi, but the function of PARKIN in immunity remains unexplored. Here we show that PARKIN plays a role in ubiquitin-mediated autophagy of M. tuberculosis. Both PARKIN-deficient mice and flies are sensitive to various intracellular bacterial infections, suggesting PARKIN plays a conserved role in metazoan innate defense. Moreover, our work reveals an unexpected functional link between mitophagy and infectious disease.