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The ubiquitin ligase parkin mediates resistance to intracellular pathogens

Author

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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
    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)

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.

Suggested Citation

  • 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 & Jeffery S. Cox, 2013. "The ubiquitin ligase parkin mediates resistance to intracellular pathogens," Nature, Nature, vol. 501(7468), pages 512-516, September.
    • Handle: RePEc:nat:nature:v:501:y:2013:i:7468:d:10.1038_nature12566
    DOI: 10.1038/nature12566
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    Cited by:

    1. David Pajuelo & Uday Tak & Lei Zhang & Olga Danilchanka & Anna D. Tischler & Michael Niederweis, 2021. "Toxin secretion and trafficking by Mycobacterium tuberculosis," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. João Fevereiro & Nikta Sajjadi & Alexandra G Fraga & Pedro M Teixeira & Jorge Pedrosa, 2020. "Individual and clinical variables associated with the risk of Buruli ulcer acquisition: A systematic review and meta-analysis," PLOS Neglected Tropical Diseases, Public Library of Science, vol. 14(4), pages 1-21, April.

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