The tetraspanin protein family includes more than 30 members, and tetraspanins have been found on the plasma membrane or in endosomal or lysosomal compartments of almost all cell types . The tetraspanin family includes distinct proteins characterized by their common specific molecular structure (Figure 1), represented by four transmembrane domains containing conserved polar residues; a small extracellular loop (SEL) and large extracellular loop (LEL) with 4, 6, 7 or 8 conserved cysteine residues; and short cytoplasmic tails [2–6]. Polar residues stabilize the tertiary structure . Tetraspanins are usually post-translationally modified by glycosylation in extracellular domains and palmitoylation at intracellular cysteines . They also contain a tyrosine-based sorting motif for intracellular compartment targeting that may mediate internalization via associated proteins . Tetraspanins are generally accepted to have an important role as organizers of each other and of distinct transmembrane and cytosolic proteins (integrins, members of the immunoglobulin superfamily, proteases) into a multimolecular membrane network called the tetraspanin web [6,9–12]. In general, tetraspanins are implicated in many cellular processes, such as cell adhesion , regulation of cell motility, and/or morphology, fusion, signaling, and other functions [10,14–17].
Figure 1. Illustrative schema of tetraspanin structure. Tetraspanin proteins traverse the plasma membrane (PM) four times, thus, defining the four transmembrane domains (TM1, TM2, TM3, TM4) with conserved polar residues (PRs) in their structure. In the extracellular space, the small (SEL) and large (LEL) extracellular loops can be recognized. The LEL contains a highly conserved CCG motif and possibly an additional two, four, five, six, or eight conserved cysteine residues (Cys). Between the cysteine residues, two disulfide bridges that enable folding of the LEL can be formed. Tetraspanins are post-translationally modified by glycosylation (G) in the large or small extracellular domain and palmitoylation (P) at the intracellular cysteine residues. Short N-terminal and C-terminal tails are oriented intracellularly.
2. Extracellular vesicles
Based on published data, the term extracellular vesicles (EVs) denotes a population of different groups of vesicles classified according to their biogenesis and release pathway, evidently overlapping in some cases. Individual membrane vesicle categories differ, not only in origin, size, and morphology, but also in content  (Figure 2). The currently known data regarding the molecular cargo of extracellular vesicles (lipids, RNAs, and proteins) are summarized in the ExoCarta database [19–21] and in Vesiclepedia, a compendium for EVs [22,23]. Based on their diameter, EVs can be classified into several groups, namely, ectosomes, or shedding microvesicles (MVs) (100–1000 nm) [24–26]; exosomes (EXs) (30–100 nm) ; apoptotic bodies (ABs) (50–5000 nm) [27,28]; and other EV subsets, as reported by Shah et al. . These groups of extracellular vesicles also differ in their origin . Exosomes have an endocytic origin and are released from multivesicular endosomes. The biogenesis of EXs begins with the internalization of molecules via endocytosis . Subsequently, endocytosed molecules are either recycled to the plasma membrane or trafficked to multivesicular bodies . Multivesicular bodies fuse with the plasma membrane, leading to the release of intraluminal vesicles as exosomes into the extracellular microenvironment . Whereas, MVs are formed by blebbing of the plasma membrane and subsequent fission of the membrane blebs [18,33], ABs are shed from the membrane of cells during the process of programmed cell death or apoptosis [18,28].
Figure 2. Extracellular vesicles: Their origin, size, and cargo. ESCRT-endosomal sorting complex required for transport; ALIX-protein regulating cellular mechanisms, including endocytic membrane trafficking and cell adhesion; TSG101-tumor susceptibility gene 101 protein; HSP-heat shock protein, CD-cluster of differentiation; RAB-proteins included in regulation of endocytosis and secretory processes, C3b-complement component.
While it is generally accepted that the main function of EVs is the mediation of intercellular communication [34–36], they are also involved in cell homeostasis, coagulation, and waste management . Although cells typically release several major EV populations defined by biophysical properties and biological functions, the heterogeneity among them is obvious and likely underlies the specific role of EV subpopulations in individual cellular processes . EVs are effective intercellular transporters of proteins, lipids, and nucleic acids. The protein cargo of extracellular vesicles includes proteins participating in cell adhesion (integrins, ICAM (intracellular adhesion molecule)), intracellular trafficking (GTPases, RAB (proteins included in regulation of endocytosis and secretory processes, annexins), and signal transduction (protein kinases, G proteins, β catenin) . EVs are usually enriched in tetraspanin proteins (mainly CD9, CD63, and CD81) and other proteins, such as ALIX (protein regulating cellular mechanisms), TSG101 (tumor susceptibility gene 101 protein), MHC1 (major histocompatibility complex 1), and HSP90 (heat shock protein 90) [39,40]. Regarding lipids, EVs are characterized by the presence of phosphatidylserine, cholesterol, sphingomyelins, and ceramides [41,42], which participate not only in intercellular signaling, but also ensure structural stability . EVs may also carry nucleic acids (genomic DNA, mitochondrial DNA, mRNA, miRNA, and long non-coding RNA) . Overall, EVs can alter the physiological and pathological function of recipient and parent cells through the transfer of proteins, lipids, and RNA . Exosome uptake (and likely uptake of the other types of EVs) can cause activation, differentiation, or dedifferentiation of target cells depending on the delivered cargo . Notably, it was shown that exosomal mRNA transferred to recipient cells can be translated and that miRNA may regulate gene expression in recipient cells . Beside the somatic (body) systems, many tissues and cells of the reproductive tract release EVs, which are believed to participate in various steps of the reproduction process (reviewed in Reference ). The participation of tetraspanin family proteins, the most prevalent proteins in EVs [48–50], which are routinely used only as markers (mostly for exosomes) in mammalian fertilization, has been demonstrated [51–53].
3. Role of Tetraspanins in EV Formation
Exosomes can be formed through ESCRT (endosomal sorting complex required for transport)-dependent or ESCRT-independent pathways (reviewed in References [40,54–56]). Studies by van Niel et al.  and Chairoungdua et al.  indicated that tetraspanins may be crucial players in ESCRT-independent pathways of exosome biogenesis and secretion. It is well known that tetraspanins can modulate membranes by affecting their curvature [58–61], which directly predetermines their participation in EV formation. Considering the reversed cone-like molecular shape of CD9, Umeda et al.  suggested that clustering of tetraspanin molecules could modulate membrane curvature to enable exosome budding and facilitate subsequent interaction of the C-terminal region of tetraspanins (cytoplasmic tail) with cytoskeletal actin through ezrin, radixin and moesin proteins , which may be involved in EV fission from the parent cell membrane.
4. Role of Tetraspanins in EV Cargo Selection, Targeting, and Uptake
Although the processes of targeting and uptake (internalization of EVs by recipient cells) are currently not fully understood, it is evident that molecules involved in tetraspanin-enriched microdomains of EVs and TEMs of recipient cells, especially tetraspanins, integrins, and other adhesion proteins, play a key role in the process of binding, fusion, and targeting of extracellular vesicles and in selective uptake of EVs by recipient cells . As shown in exosomes, the internalization of membrane molecules into endosome compartments is related to the rearrangement of TEMs . Based on previous findings, Rana et al.  hypothesized that regulation of the protein assembly of exosomes, and potentially, the recruitment of microRNA is ensured by tetraspanins. In 2012, Rana et al.  reported for the first time that selective exosome uptake by cells and tissues is critically dependent on the tetraspanin web composition. Therefore, it seems that TEMs are involved not only in molecular internalization and recycling, but that tetraspanin proteins (at least CD9, CD81, CD82, CD63, and tetraspanin-8) also regulate the sorting of proteins and possibly RNA to EVs (reviewed in Reference ). A quantitative proteomic analysis conducted by Perez-Hernandez et al.  showed that the TEM interaction network corresponds to 45% of the exosomal proteome. Consequently, the diminishment of the tetraspanin profile of extravesicular TEMs can result in a decrease in the concentration of some of their associated partners. In general, common components of TEMs within the cell membrane are tetraspanins, integrins, and other adhesion receptors and transmembrane receptor proteins [10,15,66,67]. Therefore, changes in the expression of specific tetraspanins may modulate selective targeting and uptake of EVs, thereby affecting the cellular response. Willms et al.  suggested the utilization of the tetraspanin (and integrin) profile as a distinguishing criterion for individual EV subpopulations. The involvement of tetraspanins in vesicular cargo selection was also reported in neuroblastoma cells, where EVs targeted the cells depending on the presence of CD63 tetraspanin or amyloid precursor protein . The exosomal tetraspanins CD9 and CD81, together with integrin αvβ3, were shown to be involved in the targeting and uptake of exosomes by dendritic cells, and a complex of tetraspanin-8 with integrin subunit CD49d (α4) determines the selective targeting and uptake of tumor-derived exosomes by endothelial cells . In a very recent study, Umeda et al.  revealed the cone-like molecular shape of CD9 (based on the crystal structure of CD9 and cryo-electron microscopy of human CD9) and proposed two potential roles of tetraspanins in exosome function. Tetraspanin clustering may directly affect membrane curvature and thereby enable exosome budding, or alternatively, tetraspanins can control vesicular cargo sorting through association with other partner proteins via EWI family proteins [62,69], thereby establishing a complex functional molecular network . To deliver proteins or nucleic acids, EVs undergo direct fusion with the target cell membrane or the endosomal compartment membrane after endocytic uptake [70–73]. The uptake of EVs can occur through several endocytic pathways, including clathrin-dependent endocytosis and clathrin-independent pathways, such as caveolin-mediated uptake, macropinocytosis, phagocytosis, and lipid raft-mediated internalization. The same authors stated that the different uptake mechanism of individual EV populations likely depends on the proteins and glycoproteins on the surface of the vesicle and the target cell (reviewed in Reference ). Based on the fact that tetraspanins are involved in many cellular processes, including vesicular and cellular fusion [10,74], they are ‘predestined’ to participate in EV binding and uptake by cells (reviewed in References [75–78]). In vitro and in vivo experiments have suggested that exosomes diffuse throughout the whole body, with selective enrichment in different cells/organs depending on exosome-tetraspanin complexes and cell ligands . These findings were supported by experiments on somatic cells, where a reduction in EV uptake by target/recipient cells was observed after treatment with antibodies against tetraspanin-8, CD9, CD81, and CD151 [79–81]. It should be noted that in some cases, a cellular response, such as activation/inhibition of signaling pathways, may be induced by EVs without their internalization, as has been illustrated in several studies [82–87]. It is generally believed that tetraspanins act as regulators of the adhesive activity of several adhesion molecules, including integrins [88–94], and thus, they may not only control adhesion, but may also affect signaling pathways. Therefore, specific tetraspanin and integrin profiles of EVs could ensure the specific role of individual EV subpopulations.
5. Role of Tetraspanins in Immunostimulatory and Immunosuppressive Properties of EV Subpopulations in Cancer
In recent years, great effort has been devoted to the elucidation of EV function in cancer biology (reviewed in References [95,96]). Numerous EVs secreted by cancer cells transport their molecular content to various target cells, including endothelial, epithelial, and immune cells, and serve as regulators of intercellular communication of cancer cells [95,97]. Increasing experimental data indicate a crucial role of EVs in cancer progression. On the other hand, several studies have suggested that non-tumoral cells may suppress cancer initiation and progression via EVs (reviewed in Reference ). Extracellular vesicles can participate in remodeling of the tumor microenvironment, which affects endothelial cells, epithelial cells, stromal cells, fibroblasts, and macrophages [98–100]. Findings regarding tetraspanins and integrins are also related to their role in organotropism, the non-random distribution of metastases in an organ-specific pattern [50,98,101]. Hoshino et al.  suggested that integrins in EVs mediate not only their adhesion to recipient cells, but also trigger signaling and inflammatory responses in recipient cells, thereby leading organs to become permissive for metastatic cell growth. As reported by Yue et al. , the communication between tumor-derived EVs and the matrix is also significantly affected by the interaction of tetraspanins (CD151 and tetraspanin-8) with integrins, and proteases. In addition, EVs can mediate hematopoietic and stromal cell activation, including (lymph) angiogenesis, and stimulate epithelial-mesenchymal transition in neighboring non-metastatic tumor cells .
6. Role of EV Tetraspanins in Antigen Presentation
Most immune system cells (likely all), including antigen-presenting cells (APCs), secrete extracellular vesicles, and depending on the type and status of the parent cell, EVs may modulate the immune response in various ways (initiation, expansion, maintenance, or silencing) . Professional antigen-presenting cells mainly include dendritic cells, macrophages, and B cells. It was shown that EVs released by APCs can induce an adaptive immune response by the distribution of MHC-peptide complexes and presentation of these antigens to specific T cells ( [32,103,104], as reviewed in Reference ). As known molecular organizers, tetraspanins present on the surface of immune cells have been shown to play an important role in the adaptive immune response via involvement in antigen presentation and formation of molecular complexes in immunological synapse assembly [74,105–110]. The interaction of the APC tetraspanins CD9, CD37, CD53, CD81, and CD82 with MHC molecules, as well as engagement of MHC-peptide complexes in TEMs, has led to the consideration of their role in the formation of MHC-II multimers and enhanced antigen presentation [107,111–114]. According to Kropshofer et al. , the organization of MHC-II complexes in TEMs could determine the composition of the immunological synapse, and subsequently, the quality of the T helper cell response. Andreu and Yáñez-Mó  suggested that in addition to regulation of the expression and sorting of MHC to EVs, tetraspanins may be responsible for the degree of MHC complex clustering in EV membranes sufficient to induce an immune response. Tetraspanins can also participate in the regulation of different steps in the immune response through their ability to alter the function of their associated partners (reviewed in Reference ). The evidenced or predicted involvements of tetraspanins in EV functions in somatic cells are summarized in Figure 3.
Figure 3. Evidenced/predicted involvement of tetraspanins in EV functions in somatic cells. EVs-extracellular vesicles, ESCRT-endosomal sorting complex required for transport; ?-predicted role.
Extensive research in the field of extracellular vesicles has shown their participation via their molecular cargo in many cellular functions in mammals. Although currently, tetraspanin proteins are applied mostly as markers of extracellular vesicles, increasing evidence points to their pivotal role in EV biogenesis, cargo selection, cell targeting, and uptake, which underlies their effect on distinct cellular processes under both physiological and pathological conditions. Understanding the enigmatic role of EV tetraspanins is challenging, due to their complexity. Their individual abundance differs among species, individuals, organs, and anatomical regions. Researchers working in the field of EV tetraspanins face many difficulties related to their function in multimolecular complexes. Their composition likely differs depending on the processes in which they are involved. In sum, the constantly updated knowledge regarding extracellular vesicles has provided substantial findings that markedly change the point of view on physiological, as well as pathological processes, and the contribution of EV tetraspanins should not be omitted.
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