Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis
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 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.
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Proteomics analysis of purified phagosome membranes in cells that have taken up differing cargoes by phagocytosis revealed that absence of TLR signaling leads to failure of LC3 recruitment to phagosome membranes.
“Proteomics analysis of purified phagosome membranes in cells that have taken up differing cargoes by phagocytosis has revealed that the absence of TLR signaling leads to failure of LC3 recruitment to phagosome membranes [18,39].”
From LC3-Associated Phagocytosis (LAP): Connections with Host Autophagy (2012) · cites this paper as [18]
In LAP, LC3 is recruited directly to the single-membrane phagosome, distinct from conventional autophagy where LC3 is incorporated into the double-membrane autophagosome.
“In LAP, distinct from the conventional autophagic pathway where LC3 is incorporated into the double-membrane autophagosome, LC3 is recruited directly to the single-membrane phagosome [12,16,18].”
From LC3-Associated Phagocytosis (LAP): Connections with Host Autophagy (2012) · cites this paper as [18]
Engulfment of Escherichia coli and yeast by RAW macrophage-like cells expressing GFP-LC3 induced translocation of LC3 to phagosomes within 5 to 10 minutes of internalization.
“The first report of such recruitment showed that the engulfment of Escherichia coli and yeast by RAW macrophage-like cells expressing GFP-LC3 induced the translocation of LC3 to phagosomes within 5 to 10 minutes of internalization of microorganisms [18].”
From LC3-Associated Phagocytosis (LAP): Connections with Host Autophagy (2012) · cites this paper as [18]
The newly formed phagosome is rapidly decorated by LC3.
“The newly formed phagosome is rapidly decorated by LC3 [18] (Figure 2A).”
From LC3-Associated Phagocytosis (LAP): Connections with Host Autophagy (2012) · cites this paper as [18]
Once engulfed, entotic cells are often eliminated by a RCD subroutine independent of BCL2 proteins and caspases, but relying at least in part on LC3-associated phagocytosis.
“Once engulfed, entotic cells are often eliminated by a RCD subroutine that occurs independently of BCL2 proteins and caspases [694, 704], but relies (at least in part) on a specific autophagy-related process commonly known as LC3-associated phagocytosis (LAP) [509, 705, 706].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [706]
A noncanonical autophagy pathway, termed LC3-associated phagocytosis (LAP), links activation of certain PRR with phagosome biogenesis and inflammatory cytokine responses.
“A noncanonical autophagy pathway, termed LC3-associated phagocytosis (LAP), links activation of certain PRR with phagosome biogenesis and inflammatory cytokine responses (252).”
From Aspergillus fumigatus and Aspergillosis in 2019 (2019) · cites this paper as [252]
LAP was first identified about a decade ago in studies on phagocytosis of pathogens and dead cells by immune cells.
“LAP was first identified about a decade ago in studies on phagocytosis of pathogens and dead cells by immune cells (Sanjuan et al., 2007; Martinez et al., 2011) (Fig. 9).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Sanjuan et al., 2007
LAP is a process in which the single membranes of phagosomes directly associate with LC3.
“We previously described a process in macrophages (Martinez et al., 2011; Sanjuan et al., 2007) and plasmacytoid dendritic cells (Henault et al., 2012) in which the single membranes of phagosomes directly associate with LC3, a phenomenon we called LC3-associated phagocytosis (LAP) (Sanjuan et al., 2009).”
From Noncanonical autophagy promotes the visual cycle (2013) · cites this paper as Sanjuan et al., 2007
POS phagocytosis promotes a non-canonical form of autophagy (LAP) that is dependent on LC3 and Atg5 but is not classical autophagy which requires Ulk1, Fip200, and Atg13.
“This supports the idea that POS phagocytosis promotes a non-canonical form of autophagy (i.e. LAP) that is dependent on LC3 and Atg5 but is not classical autophagy which requires Ulk1, Fip200, and Atg13 (Martinez et al., 2011; Sanjuan et al., 2007; Sanjuan et al., 2009).”
From Noncanonical autophagy promotes the visual cycle (2013) · cites this paper as Sanjuan et al., 2007
LAP is engaged by engulfment of particles that stimulate TLR-1/2, 2/6, 3, or 4, Fc-receptors, or upon engulfment of dying cells.
“LAP is engaged by the engulfment of particles that stimulate Toll-like receptors (TLR)-1/2, 2/6, 3, or 4 (Sanjuan et al., 2007), Fc-receptors (Henault et al., 2012; Huang et al., 2009), or upon engulfment of dying cells (Martinez et al., 2011).”
From Noncanonical autophagy promotes the visual cycle (2013) · cites this paper as Sanjuan et al., 2007
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- Authors
- Sanjuan, M. A., Dillon, C. P., Tait, S. W. G., Moshiach, S., Dorsey, F., Connell, S., Komatsu, M., Tanaka, K., Cleveland, J. L., Withoff, S., & Green, D. R.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Scripps Research Institute (US)
- Corresponding author
- Green, Douglas R.
- ORCID
- Venue
- Nature
- Published
- 2007-12
- Volume
- 450
- Issue
- 7173
- Pages
- 1253-1257
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2088140877
- Cited by
- 1,347
- References
- 30
- Citations by year
- 2026: 34 · 2025: 63 · 2024: 67 · 2023: 61 · 2022: 79 · 2021: 83 · 2020: 88 · 2019: 77 · 2018: 85 · 2017: 85 · 2016: 104 · 2015: 75 · 2014: 79 · 2013: 91 · 2012: 79
- FWCI
- 33.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- Toll-like receptor signaling, macrophages, autophagy, phagocytosis, phagosome maturation, autophagosomes, LC3, ATG5, ATG7, Beclin-1, phosphatidylinositol 3-kinase, lysosome fusion, phagosome acidification, pathogen killing, innate immunity
- MeSH terms
- Beclin-1, Autophagy-Related Protein 5, Autophagy-Related Protein 7, Animals, Autophagy, Macrophages, Microtubule-Associated Proteins, Phagosomes, Proteins, Saccharomyces cerevisiae, Signal Transduction, Phosphatidylinositol 3-Kinases, Apoptosis Regulatory Proteins, Toll-Like Receptors, Toll-Like Receptor 2, Mice
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