There are 33 mammalian tetraspanin proteins, each with characteristic structural features, including a conserved CCG motif in the large extracellular loop. Genetic evidence in fungi, worms, flies, mice and humans establishes that tetraspanins have key roles in many processes including development, fertilization, invasion and immune-cell function. Tetraspanins, which are expressed on nearly all cell and tissue types, also modulate cell morphology, motility, invasion, fusion, adhesion strengthening, signalling and protein trafficking.
Tetraspanins organize laterally, into tetraspanin-enriched microdomains (TEMs). At the core of TEMs are tetraspanins engaging in direct protein–protein interactions with themselves and other proteins, including the immunoglobulin superfamily members EWI-2 and EWI-F, Claudin-1, epidermal growth factor receptor (EGFR) membrane-bound ligands, integrins and Syntenin-1. These primary complexes are then joined into a network of looser secondary interactions involving many additional proteins. Tetraspanins and many of their partner proteins (for example, integrins, EWI proteins and Claudin-1) undergo protein palmitoylation, which helps to stabilize secondary interactions within TEMs.
Tetraspanins contribute to a number of normal and pathological processes that could be targeted therapeutically. For example, CD151 may support primary tumour growth as well as metastasis and angiogenesis, whereas tetraspanins CD9 and CD81 are required for oocyte fertilization. In addition, several tetraspanins contribute to the functions of platelets and lymphocytes, thereby enhancing blood clotting and affecting numerous immune functions.
Tetraspanins make substantial contributions towards infectious-disease pathologies. For HIV-1, human T-cell lymphotropic virus type 1 and other viruses, tetraspanins affect virus-induced cell fusion events and/or virus assembly and release. In hepatocytes, tetraspanin CD81 is needed for the initial steps in hepatitis C virus binding and infection, and for invasion by sporozoites from malaria-causing parasites.
Promising in vivo results suggest that targeting of tetraspanins may be therapeutically useful for injury repair, for cancer models and for combating infectious diseases. Anti-tetraspanin monoclonal antibodies, tetraspanin-derived recombinant soluble extracellular loops and RNAi knockdown strategies have all shown potential for effective modulation of tetraspanin functions.
The tetraspanin transmembrane proteins have emerged as key players in malignancy, the immune system, during fertilization and infectious disease processes. Tetraspanins engage in a wide range of specific molecular interactions, occurring through the formation of tetraspanin-enriched microdomains (TEMs). TEMs therefore serve as a starting point for understanding how tetraspanins affect cell signalling, adhesion, morphology, motility, fusion and virus infection. An abundance of recent evidence suggests that targeting tetraspanins, for example, by monoclonal antibodies, soluble large-loop proteins or RNAi technology, should be therapeutically beneficial.
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The author gratefully acknowledges support from the National Institutes of Health grants GM38903 and CA42368.
The author declares no competing financial interests.
HUGO Gene Nomenclature Committe
A family of cell-surface transmembrane proteins (24 mammalian members), with αβ-heterodimeric structures, which function as cell adhesion molecules.
- EWI proteins
A family of four cell-surface immunoglobulin superfamily proteins, sharing a conserved glutamine-tryptophan-isoleucine (EWI) motif.
- Protein palmitoylation
Post-translational acylation of a protein, typically on an intracellular cysteine residue.
Vesicles of 50–100 nm, enriched 10-fold to 100-fold for tetraspanins, and shed from the multivesicular bodies of cells.
- Monoclonal antibody
A specific antibody produced in large quantity by a single hybrid cell clone formed in the laboratory by the fusion of a B cell with a tumour cell.
The process by which new blood vessels grow from pre-existing blood vessels.
- RNA interference
(RNAi). A form of post-transcriptional gene silencing in which expression or transfection of dsRNA induces degradation, by nucleases, of the homologous endogenous transcripts, resulting in reduction or loss of gene activity.
A member of a family of enzymes (24 members in mammals) containing a conserved aspartate-histidine-histidine-cysteine (DHHC) motif, responsible for the S-palmitoylation of proteins.
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Hemler, M. Targeting of tetraspanin proteins — potential benefits and strategies. Nat Rev Drug Discov 7, 747–758 (2008). https://doi.org/10.1038/nrd2659
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