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The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria

Nature Immunology volume 10, pages 1215–1221 (2009)Cite this article

Abstract

Cell-autonomous innate immune responses against bacteria attempting to colonize the cytosol of mammalian cells are incompletely understood. Polyubiquitylated proteins can accumulate on the surface of such bacteria, and bacterial growth is restricted by Tank-binding kinase (TBK1). Here we show that NDP52, not previously known to contribute to innate immunity, recognizes ubiquitin-coated Salmonella enterica in human cells and, by binding the adaptor proteins Nap1 and Sintbad, recruits TBK1. Knockdown of NDP52 and TBK1 facilitated bacterial proliferation and increased the number of cells containing ubiquitin-coated salmonella. NDP52 also recruited LC3, an autophagosomal marker, and knockdown of NDP52 impaired autophagy of salmonella. We conclude that human cells utilize the ubiquitin system and NDP52 to activate autophagy against bacteria attempting to colonize their cytosol.

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Figure 1: The TBK1 adaptor Nap1 is recruited to ubiquitin-coated S. Typhimurium and binds ubiquitin indirectly.
Figure 2: NDP52, a ubiquitin-binding component of TBK1 complexes.
Figure 3: Ubiquitin-coated S. Typhimurium recruit NDP52.
Figure 4: NDP52 senses the bacterial ubiquitin coat.
Figure 5: S. Typhimurium recruits NDP52-containing TBK1 complexes.
Figure 6: NDP52 and TBK1 restrict growth of S. Typhimurium.
Figure 7: NDP52 binds LC3 and recruits ubiquitin-coated S. Typhimurium into autophagosomes.

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Acknowledgements

We thank F. Begum and S.-Y. Peak-Chew for mass spectrometry, J. Kendrick-Jones (Medical Research Council Laboratory of Molecular Biology) for NDP52 antiserum, D. Holden (Imperial College London), C. Tang (Imperial College London), S. Sriskandan (Imperial College London) and C. Bryant (University of Cambridge) for bacterial strains and advice, A. Geerlof (European Molecular Biology Laboratory Heidelberg) for pETM plasmid, and D. Fearon, P. Lehner and D. Komander for comments.

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  1. Grigory Ryzhakov

    Present address: Present address: Kennedy Institute of Rheumatology, Imperial College London, London, UK.,

  2. Teresa L M Thurston, Grigory Ryzhakov and Stuart Bloor: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Protein and Nucleic Acid Chemistry, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK

    Teresa L M Thurston, Grigory Ryzhakov, Stuart Bloor, Natalia von Muhlinen & Felix Randow

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T.L.M.T., G.R., S.B. and N.v.M. performed experiments and analyzed data. F.R. designed the overall research and wrote the manuscript.

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Correspondence to Felix Randow.

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Thurston, T., Ryzhakov, G., Bloor, S. et al. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat Immunol 10, 1215–1221 (2009). https://doi.org/10.1038/ni.1800

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