TLR signaling: Promptly promoting pathogen phagocytosis
 |
Exclusive to Signaling Gateway
 |
|
Simulation of the Toll-like receptor (TLR) in human macrophages promotes phagocytosis of extracellular organisms by stimulating signaling pathways traditionally associated with autophagy.
Autophagy and phagocytosis are discrete but related processes that are important for cellular defense from pathogens. Phagocytosis entails the engulfment and internalization of extracellular organisms, whereas autophagy involves the formation of a double-membrane barrier around proteins, pathogens or organelles already present in the cytosol. The phagosome or autophagosome then fuses with lysosomes and its contents are destroyed. Reporting in Nature, Sanjuan et al. now show that Toll-like receptor (TLR) signaling engages traditional autophagy components to promote phagocytosis, providing evidence for a previously unappreciated molecular connection between the two processes.
 | |
The microtubule-associated protein LC3 is enriched in mammalian macrophage autophagosomes and is a well-established autophagosome marker. In agreement with previous studies, stimulation of TLRs with lipopolysaccharide (LPS), zymosan or other ligands resulted in LC3 recruitment to autophagosomes. However, TLR signaling also promoted phagocytosis, as microscopic beads coated with LPS were quickly phagocytosed with concurrent accumulation of LC3 at the phagosome. Phagosomes containing uncoated beads occasionally fused with lysosomes, but phagocytosed beads coated with zymosan or another TLR ligand underwent rapid lysosomal fusion. Macrophages derived from Tlr2-deficient mice displayed a diminished accumulation of phagocytic LC3 in response to the TLR2 ligand zymosan, implicating TLR2 as a key mediator of phagocytosis. TLR2-mediated recruitment of LC3 to the phagosome was not affected by induction of autophagy, showing that these two pathways affect discrete responses despite a common upstream activator.
The authors next examined the individual molecular components of the autophagy pathway and found that TLR signaling usurped autophagy pathway proteins to promote phagocytosis. Previous studies demonstrated that the formation of a complex containing Beclin1 and the class III phosphatidyl-inositol-3-OH kinase (PI(3)K) Vps34 and subsequent generation of PtdIns(3,4,5)P3 is a prerequisite for autophagy. Interestingly, PtdInsP3 levels increased at the phagosome immediately following phagocytosis in a TLR-dependent manner. Live cell analyses also showed that Beclin1 was recruited to zymosan-containing phagocytes. In addition, the autophagosome pathway components ATG5 and ATG7 were essential for LC3 recruitment to phagosomes. Depletion of ATG5 or ATG7 also inhibited lysosome fusion and subsequent destruction of engulfed organisms. These data suggest that autophagy and phagocytosis stimulate a common cohort of signaling molecules.
Therefore, TLR signaling can expropriate the traditional autophagosome pathway to promote phagocytosis, lysosome fusion and the destruction of extracellular organisms. These data provide an interesting example of the economical nature of subcellular signaling pathways; one shared pathway can be altered and refined to promote a myriad of biological effects.
Emily J. Chenette
Signaling Gateway
Reference
- Sanjuan, M. A. et al. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450, 1253-1257 (2007) | Article | PubMed |
 more stories
| 
