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ER-mediated phagocytosis: a new membrane for new functions

Key Points

  • Proteomic analysis of highly purified latex-bead-containing phagosomes has shown the presence of several proteins from the endoplasmic reticulum (ER). This indicated that the ER was either a contaminant or an unexpected, genuine part of phagosomes.

  • In-depth analysis showed that the ER is recruited to the cell surface and fuses with the plasma membrane to form phagosomes during phagocytosis. This process is known as 'ER-mediated phagocytosis'.

  • After their formation, phagosomes mature into phagolysosomes. Phagolysosome biogenesis is a complex process involving transient interactions ('kiss and run') between phagosomes and endocytic organelles.

  • The presence of lipid microdomains (lipid rafts) on the phagosome membrane indicates that specialized functions of this organelle, possibly including fusion, could take place on specific regions of the membrane.

  • ER-mediated phagocytosis provides an explanation for several unanswered questions of immunobiology, including the ability of professional phagocytes to internalize particles larger than themselves, and the role of certain ER molecules in phagocytosis.

  • The ER origin of phagosomes might explain how antigens from intracellular pathogens can be presented by MHC class I molecules.

Abstract

Genomics and other high-throughput approaches, such as proteomics, are changing the way we study complex biological systems. In the past few years, these approaches have contributed markedly to improving our understanding of phagocytosis. Indeed, the ability to study biological systems by monitoring hundreds of proteins provides a level of resolution that is not attainable by the usual 'one protein at a time' approach. In this article, I discuss how proteomic approaches have revealed surprising findings that enable us to revisit established concepts, such as the origin of the phagosome membrane, and to propose new models of cell organization and the link between innate and adaptive immunity.

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Figure 1: Phagocytosis and biological membranes.
Figure 2: An updated version of the virtual phagosome.
Figure 3: ER-mediated phagocytosis: a new membrane for new functions.
Figure 4: ER-mediated phagocytosis and cross-presentation.
Figure 5: Phagocytosis and pathogen subversion.

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Acknowledgements

I wish to thank E. Gagnon for critical reading of the manuscript and his help with the figures. I also thank G. Goyette, M. Houde and J.-F. Dermine for their comments. My work is supported by Genome-Canada and Genome-Quebec, and by the Canadian Institute for Health Research.

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DATABASES

LocusLink

amphiphysin II

BIP/GRP78

C1Q

calnexin

calreticulin

CD91

CDC42

CR3

dynamin

EEA1

ERp57

FcγRIIA

flotillin 1

PDI

PGRP-LC

RAB5

RAB7

RAC

RAP1

SEC22

SEC61

VAV

Glossary

LECTINS

A family of proteins that recognize specific glycosylation patterns. They are often used as chaperones in various cellular processes.

PHAGOCYTIC CUP

A structure formed at the base of particles bound to the cell surface during phagocytosis. It is formed by the reorganization of cytoskeletal elements and the plasma membrane, allowing pseudopodia formation and elongation.

PSEUDOPODIA

Finger-like elongations of the cell surface that are used to engulf particles initially during phagocytosis.

ENDOCYTOSIS

A process that allows cells to internalize fluids and small molecules from the external milieu. Specialized forms of endocytosis can be referred to as pinocytosis or macropinocytosis for the internalization of fluids.

LYSOSOME

An intracellular organelle that was considered, for a long time, to be the end point of the endocytic apparatus. This is where the bulk of hydrolases are present for the degradation of several biomolecules.

AZUROPHILIC GRANULES

Dense lysosome-like organelles present in neutrophils. Their name comes from their colour after preparation for histological analysis. They are probably used as a source of membrane for phagosome formation in neutrophils, accounting for the rapid killing of pathogens in these cells.

PROTEOMICS

A discipline aimed at studying large numbers of proteins from tissues, cells or parts of the cell (for example, organelles). One of the approaches used to identify proteins in a high-throughput manner takes advantage of measuring the mass of peptides by mass spectrometry.

RNA INTERFERENCE

(RNAi). An approach using the expression of double-stranded RNA to interfere with the normal translation of messenger RNA into proteins. This allows the specific knock-out of proteins in various cell lines.

MASS SPECTROMETRY

An approach that allows the precise determination of the mass of charged compounds. It is routinely used to measure the mass of small molecules and proteins.

TAP TRANSPORTER COMPLEX

Transporters associated with antigen processing. Heterodimeric proteins present in the membrane of the endoplasmic reticulum that are used to transport peptides from the cytoplasm to the ER lumen. This transporter is used for the loading of peptides on MHC class I molecules.

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Desjardins, M. ER-mediated phagocytosis: a new membrane for new functions. Nat Rev Immunol 3, 280–291 (2003). https://doi.org/10.1038/nri1053

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