Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Feb 25:12:636078.
doi: 10.3389/fimmu.2021.636078. eCollection 2021.

Better Together: Current Insights Into Phagosome-Lysosome Fusion

Jenny A Nguyen  1 , Robin M Yates  1   2   3
Affiliations
Review

Better Together: Current Insights Into Phagosome-Lysosome Fusion

Jenny A Nguyen et al. Front Immunol. .

Abstract

Following phagocytosis, the nascent phagosome undergoes maturation to become a phagolysosome with an acidic, hydrolytic, and often oxidative lumen that can efficiently kill and digest engulfed microbes, cells, and debris. The fusion of phagosomes with lysosomes is a principal driver of phagosomal maturation and is targeted by several adapted intracellular pathogens. Impairment of this process has significant consequences for microbial infection, tissue inflammation, the onset of adaptive immunity, and disease. Given the importance of phagosome-lysosome fusion to phagocyte function and the many virulence factors that target it, it is unsurprising that multiple molecular pathways have evolved to mediate this essential process. While the full range of these pathways has yet to be fully characterized, several pathways involving proteins such as members of the Rab GTPases, tethering factors and SNAREs have been identified. Here, we summarize the current state of knowledge to clarify the ambiguities in the field and construct a more comprehensive phagolysosome formation model. Lastly, we discuss how other cellular pathways help support phagolysosome biogenesis and, consequently, phagocyte function.

Keywords: homeostasis; lysosome; membrane fusion; microbial clearance; phagocyte; phagosome; phagosome maturation; phagosome-lysosome fusion.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Overview of the cyclical nature of membrane fusion. Rab GTPases and their effectors recruit tethers to the membrane fusion site during the tethering step. Subsequently, SNAREs are recruited to opposing membranes and assemble in trans via the catalyzing activity of a SM protein. Once assembled, SNARE zippering drives membrane fusion. Post-fusion, NSF and α-SNAP bind to the cis-SNARE and ATP-driven complex disassembly recycles the individual SNAREs intothe cytosol for recycling.
Figure 2
Figure 2
Fusion machinery involved in phagosome maturation. (A) Working models for Rab7 recruitment and activation at the phagosome membrane during maturation: i) The Mon1-Ccz1 complex is recruited directly by PI3P and indirectly by Snx10 and NRBF2-PI3KIII/Vps34. PI3P activates the GEF activity of Mon1-Ccz1; ii) The GEF activity of PI4P-recruited HOPS activates Rab7. (B) Working model of the trans-SNARE complex mediating fusion between the late phagosome and lysosome. The small GTPase Rab7 recruits effectors RILP and Plekhm1, and concurrently with Arl8, additionally recruits the HOPS tethering complex. HOPS docks the late phagosome to the lysosome and stabilizes the trans-SNARE Stx7-Snap23-Vamp7/8 or Stx7-Vti1b-Stx8-Vamp7/8 complex at the point of membrane fusion. Note that either Plekhm1, Arl8, PI4P, or RILP on either lysosomes or phagosomes bind to HOPS Vps41 at one time, while RILP can also bind HOPS Vps39.
Figure 3
Figure 3
Duality of filamentous actin during phagosome maturation. (A) Actin delays phagolysosome biogenesis at the early phagosome maturation stage by: i) transiently assembling around nascent phagosomes when the early phagosome and/or lysosome system is overloaded with cargo thereby blocking phagosome-lysosome contact, or ii) by facilitating myosin-mediated displacement of the dynein-dynactin microtubule motor and preventing minus-end transport. (B) Actin stimulates phagolysosome biogenesis by: i) bringing the fusing organelles closer together, or ii) facilitating docking and fusion. (C) Actin polymerization at the phagosome is mediated by the ezrin-N-WASP-Arp2/3 complex binding to phagosomal PI(4,5)P2 at flotillin-1-associated lipid rafts. Cyclic actin polymerization and depolymerization is mediated by the respective phosphorylation and dephosphorylation of cofilin.
Figure 4
Figure 4
The autophagic response aids the phagocytic pathway. Phagocytosed microbes and apoptotic cells are degraded in PLs formed from the fusion of lysosomes with phagosomes. Under certain conditions, LC3 is recruited to phagosomes for LAP to create more robust PLs. Microbes that escape PL-mediated degradation are ubiquitinated in the cytosol and degraded in autophagolysosomes via xenophagy.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol (2010) 125(2 Suppl 2):S24–32. 10.1016/j.jaci.2009.07.016 - DOI - PMC - PubMed
    1. Vieira OV, Botelho RJ, Grinstein S. Phagosome maturation: aging gracefully. Biochem J (2002) 366(Pt 3):689–704. 10.1042/BJ20020691 - DOI - PMC - PubMed
    1. Desjardins M. Biogenesis of phagolysosomes: the ‘kiss and run’ hypothesis. Trends Cell Biol (1995) 5(5):183–6. 10.1016/s0962-8924(00)88989-8 - DOI - PubMed
    1. Desjardins M, Huber LA, Parton RG, Griffiths G. Biogenesis of phagolysosomes proceeds through a sequential series of interactions with the endocytic apparatus. J Cell Biol (1994) 124(5):677–88. 10.1083/jcb.124.5.677 - DOI - PMC - PubMed
    1. Fratti RA, Backer JM, Gruenberg J, Corvera S, Deretic V. Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest. J Cell Biol (2001) 154(3):631–44. 10.1083/jcb.200106049 - DOI - PMC - PubMed

Publication types

Grants and funding

LinkOut - more resources