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The tetraspanin web modulates immune-signalling complexes

Key Points

  • Tetraspanins are a large family of evolutionarily conserved membrane proteins that are expressed in a wide range of organisms.

  • The tetraspanin web describes the lateral interactions of tetraspanins and their partners in the cell membrane. Partnership with individual tetraspanins varies in different cell types but is highly specific.

  • Tetraspanins are involved in the intracellular transport of their associated partners.

  • The tetraspanin web might allow cells to attain specific and highly regulated responses to a constantly changing environment by functioning as specific membrane docks that cluster laterally associated membrane proteins with their intracellular membrane-proximal signalling components.

  • Distinct tetraspanin structural domains are associated with specific functions.

  • The state of palmitoylation modulates interactions in the tetraspanin web that result in local and temporal reorganization of tetraspanin-associated partners.

  • Tetraspanins are highly exploited by human pathogens.

Abstract

The tetraspanin web represents a new concept of molecular interactions in the immune system. Whereas most surface immune-modulating molecules involve receptor–ligand interactions, tetraspanins associate with partner proteins and facilitate their lateral positioning in the membrane. Moreover, the same tetraspanin molecule can associate with different proteins depending on the cell type. Most importantly, members of this family tend to associate with each other, together with their partners, in membrane microdomains that provide a scaffold for the transmission of external stimuli to intracellular-signalling components.

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Figure 1: Schematic structure of tetraspanins.
Figure 2: Extracellular, lateral and intracellular interactions in the tetraspanin web.
Figure 3: Schematic representation of the function of CD81 on B cells.
Figure 4: Dual role for CD81 in the antigen-presenting cell–T-cell immune synapse.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (United States). We thank J. Haimovich and R. Levy for constructive comments on this review.

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Correspondence to Shoshana Levy.

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DATABASES

Entrez Gene

CCR5

CD9

CD19

CD21

CD37

CD45

CD53

CD63

CD69

CD81

CD82

CD151

EWI2

GPR56

IL-2

RDS

ROM1

TSPAN3

TSSC6

UPIA

UPIB

VCAM1

FlyBase

Sunglasses

Glossary

TETRASPANIN PARTNER

A non-tetraspanin protein that associates directly or indirectly with a tetraspanin molecule.

CHEMICAL CROSSLINKING

A method that detects neighbouring proteins by the use of bifunctional molecular linkers.

CO-CAPPING

The accumulation of proteins in one region of a lymphocyte (cap) in response to stimulation.

FLUORESCENCE RESONANCE ENERGY TRANSFER

A method that is used to detect neighbouring molecules by measuring the reduced emission of an excited fluorescent-donor molecule in the presence of an acceptor fluorescent molecule that is excited at the emission wavelength.

S-PALMITOYLATION

A modification of proteins that results in a reversible thioester linkage of palmitic acid to cysteine residues, which increases the hydrophobicity of the protein.

DETERGENT-RESISTANT MICRODOMAINS

Cell-membrane extracts that are enriched in cholesterol, phospholipids and sphingolipids. They are liquid ordered and insoluble in non-ionic detergents.

SMALL PRE-BII CELLS

B cells at a developmental stage at which they have undergone rearrangement of immunoglobulin heavy-chain gene segments and are expressing a defined set of cell-surface markers.

ENDO-H SENSITIVE

(Endoglycosidase H sensitive). Asparagine (N)-linked high-mannose glycosylated proteins that are cleavable by endoglycosidase H. This sensitivity marks glycosylated proteins in the endoplasmic reticulum.

CHIMERIC JH-DEFICIENT MICE

Mice that are generated from blastocysts derived from JH (joining gene segment of immunoglobulin heavy chain)-deficient mice (which lack B cells). These blastocysts are injected with genetically marked embryonic stem cells.

MIXED CRYOGLOBULINAEMIA

A medical condition in which hepatitis C virus (HCV)-infected patients present with cold-precipitated complexes that contain IgM, IgG and HCV particles.

MARGINAL-ZONE B CELLS

B cells that are compartmentalized in the marginal zone of the spleen. They differ from mature circulating B cells by their phenotypic markers.

T-CELL-DEPENDENT ANTIGENS

Antigens that require T-cell–B-cell interactions to elicit a B-cell response.

T-CELL-INDEPENDENT ANTIGENS

Antigens that directly activate B cells.

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Levy, S., Shoham, T. The tetraspanin web modulates immune-signalling complexes. Nat Rev Immunol 5, 136–148 (2005). https://doi.org/10.1038/nri1548

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