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, Jeffery S. Cox

Research output: Contribution to journalArticle

252 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)512-516
Number of pages5
JournalNature
Volume501
Issue number7468
DOIs
StatePublished - 2013

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Ligases
Ubiquitin
Mitochondrial Degradation
Autophagy
Mycobacterium tuberculosis
Bacteria
Mycobacterium leprae
Salmonella typhi
Nucleic Acid Regulatory Sequences
Genetic Polymorphisms
Bacterial Infections
Diptera
Communicable Diseases
Parkinson Disease
Immunity
Mutation
Genes

ASJC Scopus subject areas

  • General

Cite this

Manzanillo, P. S., Ayres, J. S., Watson, R. O., Collins, A. C., Souza, G., Rae, C. S., ... Cox, J. S. (2013). The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature, 501(7468), 512-516. https://doi.org/10.1038/nature12566

The ubiquitin ligase parkin mediates resistance to intracellular pathogens. / Manzanillo, Paolo S.; Ayres, Janelle S.; Watson, Robert O.; Collins, Angela C.; Souza, Gianne; Rae, Chris S.; Schneider, David S.; Nakamura, Ken; Shiloh, Michael U.; Cox, Jeffery S.

In: Nature, Vol. 501, No. 7468, 2013, p. 512-516.

Research output: Contribution to journalArticle

Manzanillo, PS, Ayres, JS, Watson, RO, Collins, AC, Souza, G, Rae, CS, Schneider, DS, Nakamura, K, Shiloh, MU & Cox, JS 2013, 'The ubiquitin ligase parkin mediates resistance to intracellular pathogens', Nature, vol. 501, no. 7468, pp. 512-516. https://doi.org/10.1038/nature12566
Manzanillo PS, Ayres JS, Watson RO, Collins AC, Souza G, Rae CS et al. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature. 2013;501(7468):512-516. https://doi.org/10.1038/nature12566
Manzanillo, Paolo S. ; Ayres, Janelle S. ; Watson, Robert O. ; Collins, Angela C. ; Souza, Gianne ; Rae, Chris S. ; Schneider, David S. ; Nakamura, Ken ; Shiloh, Michael U. ; Cox, Jeffery S. / The ubiquitin ligase parkin mediates resistance to intracellular pathogens. In: Nature. 2013 ; Vol. 501, No. 7468. pp. 512-516.
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