Phagosome maturation: going through the acid test

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. Access through your

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  Download references 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). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 * Jason M. Kinchen & Kodi S. Ravichandran Authors * Jason M. Kinchen View author publications You can also search for

this author inPubMed Google Scholar * Kodi S. Ravichandran View author publications You can also search for this author inPubMed Google Scholar RELATED LINKS RELATED LINKS FURTHER

INFORMATION Kodi S. Ravichandran's homepage 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. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT

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