Activation of antibacterial autophagy by NADPH oxidases
Open accessAbstract
Autophagy plays an important role in immunity to microbial pathogens. The autophagy system can target bacteria in phagosomes, promoting phagosome maturation and preventing pathogen escape into the cytosol. Recently, Toll-like receptor (TLR) signaling from phagosomes was found to initiate their targeting by the autophagy system, but the mechanism by which TLR signaling activates autophagy is unclear. Here we show that autophagy targeting of phagosomes is not exclusive to those containing TLR ligands. Engagement of either TLRs or the Fcgamma receptors (FcgammaRs) during phagocytosis induced recruitment of the autophagy protein LC3 to phagosomes with similar kinetics. Both receptors are known to activate the NOX2 NADPH oxidase, which plays a central role in microbial killing by phagocytes through the generation of reactive oxygen species (ROS). We found that NOX2-generated ROS are necessary for LC3 recruitment to phagosomes. Antibacterial autophagy in human epithelial cells, which do not express NOX2, was also dependent on ROS generation. These data reveal a coupling of oxidative and nonoxidative killing activities of the NOX2 NADPH oxidase in phagocytes through autophagy. Furthermore, our results suggest a general role for members of the NOX family in regulating autophagy.
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LC3 can be recruited to single-membrane phagosomes in a process termed LC3-associated phagocytosis (LAP).
“Recently, it has been demonstrated that LC3 can be recruited to other membranes including single-membrane phagosomes, in a process termed LC3-associated phagocytosis (LAP).”
From LC3-Associated Phagocytosis (LAP): Connections with Host Autophagy (2012) · cites this paper as [14]
The section on FcγR- and TLR-induced recruitment reports LC3 on phagosomes, including phagosomes containing IgG-coated beads. Our copy does not specify that these phagosomes have a single membrane or call the process LC3-associated phagocytosis (LAP). (LLM, conf=0.82)
Experimental — accuracy not yet measuredInfection of phagocytic neutrophils or non-phagocytic MEF cells expressing GFP-LC3 by Salmonella typhimurium resulted in recruitment of GFP-LC3 to bacteria-containing phagosomes.
“Similarly, infection of either phagocytic neutrophils or non-phagocytic mouse embryonic fibroblast (MEF) cells, each expressing GFP-LC3, by Salmonella typhimurium also resulted in the recruitment of GFP-LC3 to bacteria-containing phagosomes [14,33].”
From LC3-Associated Phagocytosis (LAP): Connections with Host Autophagy (2012) · cites this paper as [14]
The NOX2-Generated ROS section (page unavailable) reports that GFP-LC3-expressing neutrophils infected with S. Typhimurium had LC3 colocalized with bacteria in LAMP1-positive phagosomes. The Materials and Methods section (page unavailable) lists the cell lines used, but our copy does not report the claimed Salmonella experiment in mouse embryonic fibroblasts. (LLM, conf=0.89)
Experimental — accuracy not yet measuredActivation of NOX2 NADPH oxidase by TLRs or Fcγ receptors to produce microbiocidal ROS resulted in recruitment of LC3 to the phagosome.
“Moreover, Huang et al. [14] showed that the activation of NOX2 NADPH oxidase by TLRs or Fcγ receptors (FcγR) in order to produce microbiocidal reactive oxygen species (ROS) resulted in the recruitment of LC3 to the phagosome.”
From LC3-Associated Phagocytosis (LAP): Connections with Host Autophagy (2012) · cites this paper as [14]
Host defense against microbial infection involves recruitment of LC3 to phagosomes, promoting their maturation and microbial killing.
“Similarly, host defense against microbial infection involves the recruitment of LC3 to phagosomes, promoting their maturation and microbial killing (Henault et al., 2012; Huang et al., 2009).”
From Noncanonical autophagy promotes the visual cycle (2013) · cites this paper as Huang et al., 2009
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 Huang et al., 2009
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Florey, O., Kim, S., & Overholtzer, M. (2015) · Current Molecular Medicine · doi:10.2174/1566524015666151026100042 · Cited by 45 · see citing works
Kim, J. H., Lee, J., Bae, S.-J., Kim, Y., Park, B.-J., Choi, J.-W., Kwon, J., Cha, G.-H., Yoo, H. J., Jo, E.-K., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-06610-4 · Cited by 45 · see citing works
Autophagy proteins regulate cell engulfment mechanisms that participate in cancer
Kim, S. E., & Overholtzer, M. (2013) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2013.05.004 · Cited by 35 · see citing works
- Authors
- Huang, J., Canadien, V., Lam, G. Y., Steinberg, B. E., Dinauer, M. C., Magalhaes, M. A. O., Glogauer, M., Grinstein, S., & Brumell, J. H.
- Affiliations
- Hospital for Sick Children (CA)
- Indiana University School of Medicine (US)
- Faculty of Dentistry,
- University of Toronto (CA)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-04-14
- Volume
- 106
- Issue
- 15
- Pages
- 6226-6231
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2664152
- OpenAlex
- W2117137379
- Cited by
- 556
- References
- 36
- Citations by year
- 2026: 11 · 2025: 22 · 2024: 16 · 2023: 18 · 2022: 23 · 2021: 30 · 2020: 43 · 2019: 44 · 2018: 31 · 2017: 43 · 2016: 40 · 2015: 36 · 2014: 48 · 2013: 44 · 2012: 35
- FWCI
- 24.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- TSpace (University of Toronto) (submittedVersion)
- Funders
- Burroughs Wellcome Fund
- Ontario Innovation Trust
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- antibacterial autophagy, NADPH oxidase, NOX2, reactive oxygen species, phagosome maturation, Toll-like receptors, Fc gamma receptor, phagocytosis, epithelial cells, innate immunity, oxidative killing
- MeSH terms
- Animals, Autophagy, Cell Line, Epithelial Cells, Humans, Phagosomes, Receptors, Antigen, T-Cell, Salmonella typhimurium, Signal Transduction, Reactive Oxygen Species, Receptors, IgG, NADPH Oxidases, Mice
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