Key Points
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Lipid rafts are liquid-ordered membranes, enriched in cholesterol and sphingolipids, that can selectively incorporate or exclude proteins. This allows them to regulate many protein–protein and lipid–protein interactions at the cell surface.
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Lipid rafts function as concentration points for B- and T-cell receptor signalling, contributing to the adaptive immune response against pathogens. By organizing signalling downstream of Toll-like receptors, lipid rafts are also involved in the innate immune response.
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Despite the role of rafts in the activation of the immune system, many viruses, bacteria and protozoan parasites can use these host microdomains to infect target cells.
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Intracellular pathogens hijack host rafts to find gateways for entry into the cell, to create sheltered environments in which to replicate, to prevent host immune responses by taking over signalling pathways or to generate areas in which new pathogens can be assembled efficiently.
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Several pathogens, of which HIV and Epstein–Barr virus are well-studied examples, have strategies to subvert raft-associated signalling. This enables their efficient replication in immune cells while blocking the immune response that is elicited by the target cells.
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Molecular dissection of the mechanisms by which microorganisms hijack host raft domains will provide new therapeutic insights for the prevention and/or treatment of certain infectious diseases.
Abstract
Throughout evolution, organisms have developed immune-surveillance networks to protect themselves from potential pathogens. At the cellular level, the signalling events that regulate these defensive responses take place in membrane rafts — dynamic microdomains that are enriched in cholesterol and glycosphingolipids — that facilitate many protein–protein and lipid–protein interactions at the cell surface. Pathogens have evolved many strategies to ensure their own survival and to evade the host immune system, in some cases by hijacking rafts. However, understanding the means by which pathogens exploit rafts might lead to new therapeutic strategies to prevent or alleviate certain infectious diseases, such as those caused by HIV-1 or Ebola virus.
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Acknowledgements
We thank S. Jiménez-Baranda, E. Mira, R. A. Lacalle, C. Gómez and P. Lucas for their contribution to part of the data that are presented here and for helpful discussion, and C. Mark for editorial assistance. The authors apologize to those researchers whose work has not been cited owing to space limitations. Our work is supported by grants from the Spanish MCyT/FEDER (Ministerio de Ciencia y Tecnologia/Fondos Europeos de Desarrollo Regional). The Department of Immunology and Oncology was founded and is supported by the Spanish Council for Scientific Research (CSIC) and by Pfizer.
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Glossary
- IMMUNE SYNAPSE
-
A structure that is formed at the cell surface between a T or B cell and an antigen-presenting cell; also known as the supramolecular activation cluster (SMAC). Important molecules that are involved in T- or B-cell activation — including the T- or B-cell receptor, numerous signal-transduction molecules and molecular adaptors — accumulate at this site. The formation of the immune synapse requires mobilization of the actin cytoskeleton.
- NYSTATIN
-
An antibiotic obtained from Streptomyces noursei that binds to cholesterol in the cell membrane. It is presently used in anti-fungal drug therapy for infection with Candida albicans.
- FLUORESCENCE RESONANCE ENERGY TRANSFER
-
(FRET). A technique that is used to analyse intermolecular interactions on the basis of the energy transfer from a donor molecule to an acceptor molecule without the emission of a photon. Using microscopic or flow-cytometry-based methods, proteins that are fused to fluorescent proteins are assessed for their interaction by measuring the energy transfer between fluorophores.
- FIMH
-
An Esherichia coli adhesin that is encoded by the bacterial FimH gene. Adhesins are expressed by the bacterial pilus — an organelle that extends from the bacterial surface and functions to attach the bacterium to the target cell.
- TYPE III SECRETION
-
Specialized secretion systems that allow Gram-negative bacteria to target virulence factors directly to host cells. They are comprised of at least 20 genes that encode secreted effectors and the machinery required for the secretion and translocation to target cells. Chaperones are needed for secretion, and although the virulence factors differ between pathogens, the secretion machinery is often interchangeable.
- ACID SPHINGOMYELINASE
-
(ASM). A glycoprotein that functions as a lysosomal enzyme, the deficiency of which causes Niemann–Pick disease type A. A secreted and a membrane-anchored form of this enzyme have been described.
- DETERGENT-RESISTANT MEMBRANE
-
(DRM). A membrane that remains insoluble after cell lysis with cold non-ionic detergents — generally Triton X-100 is used, although Brij58 and CHAPS can also be used. DRMs are post-lysis membrane aggregates that partition in the low-density fraction in sucrose-density gradients. The DRM fraction is considered to be enriched in cholesterol-rich raft domains.
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Mañes, S., del Real, G. & Martínez-A, C. Pathogens: raft hijackers. Nat Rev Immunol 3, 557–568 (2003). https://doi.org/10.1038/nri1129
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DOI: https://doi.org/10.1038/nri1129
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