The ubiquitin ligase parkin mediates resistance to intracellular pathogens

Paolo S. Manzanillo, Janelle S. Ayres, Robert O. Watson, Angela C. Collins, Gianne Souza, Chris S. Rae, David S. Schneider, Ken Nakamura, Michael U. Shiloh and Jeffery S. Cox ()
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Paolo S. Manzanillo: University of California, San Francisco, San Francisco, California 94158, USA
Janelle S. Ayres: Immunobiology and Microbial Pathogenesis Laboratory, The Salk Institute for Biological Studies
Robert O. Watson: University of California, San Francisco, San Francisco, California 94158, USA
Angela C. Collins: University of Texas Southwestern Medical Center
Gianne Souza: University of California, San Francisco, San Francisco, California 94158, USA
Chris S. Rae: University of California
David S. Schneider: Stanford University
Ken Nakamura: Gladstone Institute of Neurological Disease, University of California
Michael U. Shiloh: University of Texas Southwestern Medical Center
Jeffery S. Cox: University of California, San Francisco, San Francisco, California 94158, USA

Nature, 2013, vol. 501, issue 7468, 512-516

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature12566

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