Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis.
Phagocytosis and autophagy are two ancient, highly conserved processes involved, respectively, in the removal of extracellular organisms and the destruction of organisms in the cytosol. 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 contents, a process that has similarities with phagosome maturation. Toll-like-receptor (TLR) engagement activates a variety of defence mechanisms within phagocytes, including facilitation of phagosome maturation, and also engages autophagy. 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.
Sanjuan
Miguel A
MA
Department of Immunology, St Jude Children's Research Institute, Memphis, Tennessee 38105, USA.
Dillon
Christopher P
CP
Tait
Stephen W G
SW
Moshiach
Simon
S
Dorsey
Frank
F
Connell
Samuel
S
Komatsu
Masaaki
M
Tanaka
Keiji
K
Cleveland
John L
JL
Withoff
Sebo
S
Green
Douglas R
DR
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D008869:Microtubule-Associated Proteins; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; C115010:Becn1 protein, mouse; C493486:Tlr2 protein, mouse