Abstract
Autophagy defends the mammalian cytosol against bacterial infection1,2,3. Efficient pathogen engulfment is mediated by cargo-selecting autophagy adaptors that rely on unidentified pattern-recognition or danger receptors to label invading pathogens as autophagy cargo, typically by polyubiquitin coating4,5,6,7,8,9. Here we show in human cells that galectin 8 (also known as LGALS8), a cytosolic lectin, is a danger receptor that restricts Salmonella proliferation. Galectin 8 monitors endosomal and lysosomal integrity and detects bacterial invasion by binding host glycans exposed on damaged Salmonella-containing vacuoles. By recruiting NDP52 (also known as CALCOCO2), galectin 8 activates antibacterial autophagy. Galectin-8-dependent recruitment of NDP52 to Salmonella-containing vesicles is transient and followed by ubiquitin-dependent NDP52 recruitment. Because galectin 8 also detects sterile damage to endosomes or lysosomes, as well as invasion by Listeria or Shigella, we suggest that galectin 8 serves as a versatile receptor for vesicle-damaging pathogens. Our results illustrate how cells deploy the danger receptor galectin 8 to combat infection by monitoring endosomal and lysosomal integrity on the basis of the specific lack of complex carbohydrates in the cytosol.
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References
Yang, Z. & Klionsky, D. J. An overview of the molecular mechanism of autophagy. Curr. Top. Microbiol. Immunol. 335, 1–32 (2009)
Deretic, V. Autophagy in immunity and cell-autonomous defense against intracellular microbes. Immunol. Rev. 240, 92–104 (2011)
Levine, B., Mizushima, N. & Virgin, H. W. Autophagy in immunity and inflammation. Nature 469, 323–335 (2011)
Birmingham, C. L., Smith, A. C., Bakowski, M. A., Yoshimori, T. & Brumell, J. H. Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole. J. Biol. Chem. 281, 11374–11383 (2006)
Johansen, T. & Lamark, T. Selective autophagy mediated by autophagic adapter proteins. Autophagy 7, 279–296 (2011)
Perrin, A., Jiang, X., Birmingham, C., So, N. & Brumell, J. Recognition of bacteria in the cytosol of mammalian cells by the ubiquitin system. Curr. Biol. 14, 806–811 (2004)
Zheng, Y. T. et al. The adaptor protein p62/SQSTM1 targets invading bacteria to the autophagy pathway. J. Immunol. 183, 5909–5916 (2009)
Thurston, T. L. M., Ryzhakov, G., Bloor, S., von Muhlinen, N. & Randow, F. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nature Immunol. 10, 1215–1221 (2009)
Wild, P. et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228–233 (2011)
Houzelstein, D. et al. Phylogenetic analysis of the vertebrate galectin family. Mol. Biol. Evol. 21, 1177–1187 (2004)
Rabinovich, G. A. & Toscano, M. A. Turning “sweet” on immunity: galectin–glycan interactions in immune tolerance and inflammation. Nature Rev. Immunol. 9, 338–352 (2009)
Paz, I. et al. Galectin-3, a marker for vacuole lysis by invasive pathogens. Cell. Microbiol. 12, 530–544 (2009)
Dupont, N. et al. Shigella phagocytic vacuolar membrane remnants participate in the cellular response to pathogen invasion and are regulated by autophagy. Cell Host Microbe 6, 137–149 (2009)
Randow, F. How cells deploy ubiquitin and autophagy to defend their cytosol from bacterial invasion. Autophagy 7, 304–309 (2011)
Shahnazari, S. & Brumell, J. H. Mechanisms and consequences of bacterial targeting by the autophagy pathway. Curr. Opin. Microbiol. 14, 68–75 (2011)
Cemma, M., Kim, P. K. & Brumell, J. H. The ubiquitin-binding adaptor proteins p62/SQSTM1 and NDP52 are recruited independently to bacteria-associated microdomains to target Salmonella to the autophagy pathway. Autophagy 7, 341–345 (2011)
Stowell, S. R. et al. Innate immune lectins kill bacteria expressing blood group antigen. Nature Med. 16, 295–301 (2010)
Patnaik, S. K. & Stanley, P. Lectin-resistant CHO glycosylation mutants. Methods Enzymol. 416, 159–182 (2006)
Shahnazari, S. et al. A diacylglycerol-dependent signaling pathway contributes to regulation of antibacterial autophagy. Cell Host Microbe 8, 137–146 (2010)
Collins, C. A. et al. Atg5-independent sequestration of ubiquitinated mycobacteria. PLoS Pathog. 5, e1000430 (2009)
Ng, A. C. Y. et al. Human leucine-rich repeat proteins: a genome-wide bioinformatic categorization and functional analysis in innate immunity. Proc. Natl Acad. Sci. USA 108, 4631–4638 (2011)
Mostowy, S. et al. Entrapment of intracytosolic bacteria by septin cage-like structures. Cell Host Microbe 8, 433–444 (2010)
Yano, T. et al. Autophagic control of Listeria through intracellular innate immune recognition in Drosophila. Nature Immunol. 9, 908–916 (2008)
Travassos, L. H. et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nature Immunol. 11, 55–62 (2010)
Cooney, R. et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nature Med. 16, 90–97 (2010)
Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411, 599–603 (2001)
McCarroll, S. A. et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nature Genet. 40, 1107–1112 (2008)
Rioux, J. D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nature Genet. 39, 596–604 (2007)
Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genet. 39, 207–211 (2007)
Ryzhakov, G. & Randow, F. SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK. EMBO J. 26, 3180–3190 (2007)
Randow, F. & Sale, J. E. Retroviral transduction of DT40. Subcell. Biochem. 40, 383–386 (2006)
Bloor, S. et al. Signal processing by its coil zipper domain activates IKKγ. Proc. Natl Acad. Sci. USA 105, 1279–1284 (2008)
Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004)
Fitzgerald, K. A. et al. IKKε and TBK1 are essential components of the IRF3 signaling pathway. Nature Immunol. 4, 491–496 (2003)
Barrios-Rodiles, M. et al. High-throughput mapping of a dynamic signaling network in mammalian cells. Science 307, 1621–1625 (2005)
Shaughnessy, L. M., Lipp, P., Lee, K.-D. & Swanson, J. A. Localization of protein kinase C ε to macrophage vacuoles perforated by Listeria monocytogenes cytolysin. Cell. Microbiol. 9, 1695–1704 (2007)
Berg, T. O., Strømhaug, P. E., Berg, T. & Seglen, P. O. Separation of lysosomes and autophagosomes by means of glycyl-phenylalanine-naphthylamide, a lysosome-disrupting cathepsin-C substrate. Eur. J. Biochem. 221, 595–602 (1994)
Acknowledgements
We thank J. Kendrick-Jones (MRC Laboratory of Molecular Biology), A. Geerlof (European Molecular Biology Laboratory Heidelberg), N. Mizushima (Tokyo University) and P. Stanley (Albert Einstein College of Medicine) for kindly sharing reagents.
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T.L.M.T., M.P.W., N.v.M., Á.F. and F.R. planned, performed and analysed experiments. T.L.M.T. and F.R. designed the overall research. F.R. wrote the manuscript.
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Thurston, T., Wandel, M., von Muhlinen, N. et al. Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482, 414–418 (2012). https://doi.org/10.1038/nature10744
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DOI: https://doi.org/10.1038/nature10744
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