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Phagosome maturation: going through the acid test

Nature Reviews Molecular Cell Biology volume 9, pages 781–795 (2008)Cite this article

Key Points

  • Eukaryotic cells engulf a variety of particles during their lifetime, including potentially pathogenic microorganisms and apoptotic cells. A person clears approximately 200 billion cells each day, making the removal of apoptotic cells one of the most common types of phagocytosis. Understanding how bacteria and apoptotic cells are phagocytosed and processed is a fundamentally important biological problem, both for normal homeostasis and disease.

  • Internalized particles are present in membrane-bound organelles that are termed phagosomes. The phagosome functions as more than just as an organelle for 'garbage disposal': proteins from the ingested target are degraded into peptides and presented on major histocompatibility complex (MHC) class II molecules (in the case of bacteria) for the generation of an immune response, whereas apoptotic cell-derived antigens are typically cross-presented on MHC class I molecules and are tolerogenic.

  • Phagosome maturation is the process by which a particle-containing phagosome 'matures' through a series of increasingly acidic membrane-bound structures, becoming an acidic phagolysosome before fusion with lysosomes. Proteomics approaches have identified a number of candidates localized to the phagosome, including the GTPases RAB5 and RAB7.

  • Recent studies in model systems, such as Drosophila melanogaster, Dictyostelium discoideum and Caenorhabditis elegans, have developed genetic models for the identification and characterization of proteins that are required for phagosome maturation. Studies in the nematode have led to the identification of a pathway for the maturation of apoptotic cell-containing phagosomes.

  • Following phagocytosis, apoptotic cells (and other particles) exist in phagosomes. The proteins on the intracellular face of the phagosome membrane change as the phagosome matures. Soon after uptake, the phagosome is coated with the GTPase RAB5, which is subsequently exchanged for RAB7 and eventually for lysosomal markers, such as LAMP1.

  • The regulation of phagosome maturation is complex, requiring a series of guanine nucleotide-exchange factors (GEFs), GTPase-activating proteins (GAPs) and effectors. How RAB5 is regulated on the phagosome in vivo is just beginning to be described. The HOPS complex, a RAB7 activator and effector, is required for the maturation of the phagosome from the RAB7-positive stage.

  • A number of different bacterial pathogens have evolved mechanisms for co-opting phagosome maturation as a means of immune evasion or as a replicative niche. These bacteria target the machinery that regulates maturation, in some cases converting the phagosome into other types of organelles.

  • Future studies are expected to focus on signalling pathways that determine whether the immune response to an internalized particle would be immunogenic (in response to bacteria) or tolerogenic (in response to apoptotic cells). The identification of novel players, and their placement within a pathway for phagosome maturation, might be important for future development of new therapeutics that target intracellular pathogens (such as Mycobacterium tuberculosis).

Abstract

Phagosome maturation is the process by which internalized particles (such as bacteria and apoptotic cells) are trafficked into a series of increasingly acidified membrane-bound structures, leading to particle degradation. The characterization of the phagosomal proteome and studies in model organisms and mammals have led to the identification of numerous candidate proteins that cooperate to control the maturation of phagosomes containing different particles. A subset of these candidate proteins makes up the first pathway to be identified for the maturation of apoptotic cell-containing phagosomes. This suggests that a machinery that is distinct from receptor-mediated endocytosis is used in phagosome maturation.

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Figure 1: Endocytosis as a paradigm for phagocytosis.
Figure 2: Activation of RAB5 during phagosome maturation.
Figure 3: Pathways for phagosome maturation and endocytosis.

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Acknowledgements

The authors wish to thank colleagues in the engulfment field and members of our laboratory for insightful discussions. This work was supported by grants from the National Institute of General Medical Sciences/National Institutes of Health and the Strategic Program for Asthma Research (K.S.R), and an Arthritis Foundation Postdoctoral Fellowship (J.M.K).

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  1. Beirne B. Carter Center for Immunology Research and the Department of Microbiology, University of Virginia, Charlottesville, 22902, Virginia, USA

    Jason M. Kinchen & Kodi S. Ravichandran

  2. Jason M. Kinchen & Kodi S. Ravichandran

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Glossary

Receptor-mediated endocytosis

The process by which a ligand-bound receptor is internalized into a membrane-bound vesicle. These vesicles sequentially acquire different Rab GTPases.

Pinocytosis

The process by which liquids and small particles are internalized by the cell.

Complement

A protein complex component of the innate immune system that can bind to foreign particles and initiate their phagocytosis.

Fc receptors

A group of proteins that bind to immunoglobulin (Ig)G-opsonized particles, leading to the activation of phagocytosis.

Rab GTPases

A family of proteins that cycle between GDP-bound inactive and GTP-bound active forms and have a role in targeting transport to membrane-bound organelles.

Recycling endosome

A membrane-bound organelle for the recycling of receptors following ligand dissociation.

Programmed cell death

The process by which a healthy cell is induced to die, undergoes apoptosis and is then cleared and degraded by a phagocyte.

Prenylated

The process by which a hydrocarbon moiety is attached to a conserved CAAX motif in the C terminus of GTPases.

Dynamin

A large GTPase that is involved in membrane scission, actin cytoskeletal dynamics and phagosome maturation.

Focal exocytosis

Small vesicles are targeted to the plasma membrane during phagocytosis. In turn, this is thought to produce a local increase in the volume of plasma membrane, thereby allowing the cell to extend its membrane around large particles.

FYVE domain

A zinc-finger-containing protein motif that binds to the membrane lipid phosphatidyl-inositol-3-phosphate. This results in the targeting of the FYVE-containing protein to the membrane.

Phox homology (PX) domain

A lipid- and protein-interaction domain that consists of 100–130 amino acids and is defined by sequences that are found in two components of the phagocyte NADPH oxidase (phox) complex.

Retrograde transport

Transport from the Golgi to the endoplasmic reticulum (ER). This process is the reverse of the normal mode of ER-to-Golgi transport.

Toll-like receptor

A transmembrane protein that recognizes bacterial pathogens and induces an inflammatory response.

ARF GTPases

(ADP-ribosylation factor). A family of small GTPases that regulate aspects of membrane trafficking that are related to the budding of vesicles from membranes.

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Kinchen, J., Ravichandran, K. Phagosome maturation: going through the acid test. Nat Rev Mol Cell Biol 9, 781–795 (2008). https://doi.org/10.1038/nrm2515

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