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Letter
Nature 450, 1253-1257 (20 December 2007) | doi:10.1038/nature06421; Received 25 September 2007; Accepted 22 October 2007
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Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis
Miguel A. Sanjuan1, Christopher P. Dillon1, Stephen W. G. Tait1, Simon Moshiach2, Frank Dorsey3, Samuel Connell1, Masaaki Komatsu4, Keiji Tanaka4, John L. Cleveland5, Sebo Withoff1 & Douglas R. Green1
- Department of Immunology,
- Department of Tumor Cell Biology, and,
- Department of Biochemistry, St Jude Children's Research Institute, Memphis, Tennessee 38105, USA
- Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan
- Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida 33458, USA
Correspondence to: Douglas R. Green1 Correspondence and requests for materials should be addressed to D.R.G. (Email: douglas.green@stjude.org).
Abstract
Phagocytosis and autophagy are two ancient, highly conserved processes involved, respectively, in the removal of extracellular organisms and the destruction of organisms in the cytosol1, 2, 3. Autophagy, for either metabolic regulation or defence, involves the formation of a double membrane called the autophagosome, which then fuses with lysosomes to degrade the contents4, a process that has similarities with phagosome maturation. Toll-like-receptor (TLR) engagement activates a variety of defence mechanisms within phagocytes5, including facilitation of phagosome maturation6, and also engages autophagy7. Therefore we speculated that TLR signalling might link these processes to enhance the function of conventional phagosomes. Here we show that a particle that engages TLRs on a murine macrophage while it is phagocytosed triggers the autophagosome marker LC3 to be rapidly recruited to the phagosome in a manner that depends on the autophagy pathway proteins ATG5 and ATG7; this process is preceded by recruitment of beclin 1 and phosphoinositide-3-OH kinase activity. Translocation of beclin 1 and LC3 to the phagosome was not associated with observable double-membrane structures characteristic of conventional autophagosomes, but was associated with phagosome fusion with lysosomes, leading to rapid acidification and enhanced killing of the ingested organism.
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