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Viruses 2014, 6(2), 875-892; doi:10.3390/v6020875
Abstract: Tetraspanins are integral transmembrane proteins organized in microdomains displaying specific and direct interactions with other tetraspanins and molecular partners. Among them, CD81 has been implicated in a variety of physiological and pathological processes. CD81 also plays a crucial role in pathogen entry into host cells, including hepatitis C virus (HCV) entry into hepatocytes. HCV is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV entry into hepatocytes is a complex process that requires the coordinated interaction of viral and host factors for the initiation of infection, including CD81, scavenger receptor BI, claudin-1, occludin, membrane-bound host cell kinases, Niemann-Pick C1 Like 1, Harvey rat sarcoma viral oncogene homolog (HRas), CD63 and transferrin receptor 1. Furthermore, recent data in HCV model systems have demonstrated that targeting critical components of tetraspanins and associated cell membrane proteins open new avenues to prevent and treat viral infection.
1.1. The Tetraspanin Family of Proteins
Tetraspanins are part of a family of transmembrane proteins with significant sequence homology that has been conserved during evolution. In mammals, there are thirty two tetraspanins and only a minority has been extensively studied. The tetraspanin family is composed of type IV glycoproteins, discovered in the late 1980s with the subsequent cloning of CD81 as a protein of 26 kDa . Tetraspanins are relatively small proteins (200–300 amino acids) composed of a small extracellular loop (SEL), a large extracellular loop (LEL), four transmembrane domains and intracellular N- and C−terminal domains [2,3]. Tetraspanins are characterized by the presence of four cysteines and a CCG motif in the LEL. The N-terminal domain forms an alpha helix containing positively charged residues important for protein interactions, as well as palmitoylation sites causing anchorage of the protein to the inner leaflet of the plasma membrane. The C-terminal domain also contains palmitoylation sites on intracellular cysteine residues , which are required for tetraspanin association with cholesterol complexes . Palmitoylated tetraspanins are important for the assembly of the tetraspanin web by linking tetraspanins and their associated proteins in cholesterol rich regions of the plasma membrane and by their association with proteins of the cytoskeleton and signaling molecules [6,7].
While all cells, except sperm cells, express tetraspanins, the expression level of the individual proteins in different tissues is variable . Some tetraspanins may be considered to be cell-specific while others are characterized by a very broad expression, without being ubiquitous. For example, the tetraspanin CD81 is expressed on hepatocytes, epithelial cells, fibroblasts, endothelial cells and on most of the blood cells, excluding erythrocytes, platelets and neutrophils. Tetraspanins form large complexes with other membrane proteins and given the heterogeneity in the composition as well as the dynamic nature of these complexes, tetraspanins are implicated in various biological processes, such as adhesion, migration, proliferation, signal transduction, intracellular trafficking and differentiation.
1.2. Interaction of CD81 with Other Host Factors
Several tetraspanins interact with other tetraspanins and partner transmembrane proteins like integrins, molecules of the immunoglobulin superfamily, cellular enzymes, signaling molecules and precursors of growth factors [5,8,9,10,11,12,13]. These interactions are direct and highly specific. Specialized regions on the surface of the cell membrane where tetraspanin interactions take place are termed as “tetraspanin-enriched microdomains” (TEMs) . The composition of TEMs is cell- and tissue-specific. Thus, in each cell type, these networks consist of different tetraspanin-associated partners, which define their function. TEMs are highly regulated structures governed by cholesterol and lipid composition, by physiological stage of the cell and by palmitoylation of putative sites in juxtamembrane domains [6,7,14].
CD81 is a key tetraspanin protein expressed in numerous cell types, either alone or as a part of TEM. It is involved in myriad of physiological functions through association with other tetraspanins and membrane proteins. Among the known interaction partners of CD81 are integrin α4β1  and members of the immunoglobulin family EWI-F and EWI-2 [16,17] that link CD81 to the actin cytoskeleton, thereby regulating cell motility and polarity [18,19]. On the surface of a B-cell, CD81 participates in forming CD19-signaling complex, which in conjunction with the B-cell antigen receptor (BCR) lowers the activation threshold of BCR, leading to antibody production in response to antigenic stimulation. While CD81 does not affect B-cell and T-cell development in CD81-knock-out mice, it regulates lymphocyte proliferation through multiple ways. Thus, CD81 deficiency results in enhanced antibody response to type II T-independent antigens but impaired antibody response to T-dependent antigens in CD81-null mice [20,21,22]. In line with this, a case study reported absence of CD19 expression in a patient with normal CD19 gene but possessing a rare homozygous CD81 gene defect as a cause of profound hypogammaglobulinemia .
Interestingly, CD81 is also able to activate intracellular signaling pathways, such as the mitogen−activated protein kinase (MAPK) pathway. Indeed, CD81 recruits Src homology 2 domain containing transforming protein (Shc) to the plasma membrane via its phosphotyrosine-binding (PTB) domain and induces activation of extracellular signal-regulated kinases (Erk) leading to tumor cell proliferation . In addition, activated protein kinase C (PKC) migrates to the plasma membrane and associates with tetraspanins CD9, CD53, CD81, CD82 and CD151 . PKC is required for integrin−mediated cell adhesion, but the formation of tetraspanin-PKC complexes is not integrin−dependent. Tetraspanins function rather as linker molecules that recruit PKC to a close proximity of integrin β1 (ITGB1) by associating ITGB1 to the extracellular domain of tetraspanins and PKC to their cytoplasmic domain .
2. Co-Receptor Association(s) and HCV Entry
2.1. CD81-HCV Interactions
Tetraspanins are not only essential for cell biology; they are also involved in various steps of pathogen infection including parasites, bacteria and viruses. The tetraspanin CD81 plays a role in Plasmodium sporozoite infection [26,27] and in Listeria monocytogenes entry . Regarding viral pathogens, it is established that CD81 is an entry factor for hepatitis C virus (HCV) [29,30,31]. Contrarily, CD81 has been shown to negatively regulate human immunodeficiency virus-1 (HIV-1) infection by modulating envelope-mediated membrane fusion .
HCV infection is a leading cause of liver cirrhosis and hepatocellular carcinoma (HCC) world-wide [33,34,35]. HCV is a small enveloped virus possessing a single-stranded positive sense RNA genome. It belongs to the hepacivirus genus within the Flaviviridae family. De novo infection of hepatocytes by HCV is facilitated by two mechanisms, namely cell-free and cell-cell transmission [36,37]. Both modes of transmission rely on the viral envelope glycoproteins E1 and E2 and several host cell entry factors including CD81, scavenger receptor class B type 1 (SR-BI), claudin-1 (CLDN1), occludin (OCLN), epidermal growth factor receptor (EGFR) and its signal transducer Harvey rat sarcoma viral oncogene homolog (HRas) [37,38,39,40,41,42]. Within the past years, the molecular mechanisms of cell-free entry and the subsequent steps of the viral life cycle have been intensively characterized. Upon interaction with specific cellular receptors via its envelope glycoproteins, HCV particles are endocytosed. In the endocytic vesicle, low pH triggers fusion of the viral and the host membranes releasing the ~9.6 Kb viral genome into the cytoplasm of the newly infected cell . The highly conserved un-translated regions (UTR) at the 5' and 3' ends mediate replication of the viral genome and translation of viral proteins. Internal ribosomal entry site (IRES)-dependent translation of HCV genome results in a ~3,010 amino acid polyprotein that is cleaved by host and viral proteases to yield 10 mature viral proteins consisting of three structural proteins (the core and glycoproteins E1 and E2), six non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) and a small integral transmembrane protein (p7). Viral replication and assembly occurs at the endoplasmic reticulum (ER) membrane and in close association with lipid droplets (LDs) [44,45,46,47]. Assembly and release of HCV particles appear to be closely linked with very low density lipoprotein (VLDL) secretory pathway [48,49,50]. The released viral particles can then infect neighboring hepatocytes via cell-free infection. Of note, these viral particles are sensitive to neutralizing antibodies targeting the viral envelope glycoproteins. In addition, assembled viral particles can also be directly transmitted from an infected cell to an adjacent cell in a process that is resistant to most of the neutralizing antibodies uncovered to date, but the underlying molecular mechanisms have not been fully characterized. While cell-free infection plays an important role during initiation of infection, cell−cell transmission is thought to play a major role during maintenance of infection and viral dissemination.
The tetraspanin CD81was the first reported host factor interacting with a soluble form of the HCV glycoprotein E2 . It was subsequently shown that CD81 is required for HCV infection of hepatocytes. Indeed, HCV entry and infectivity is inhibited in a pan-genotypic manner by CD81−specific antibodies [38,43,51,52,53,54,55], by a soluble recombinant form of the CD81 LEL [43,56], and by silencing CD81 expression . In contrast, CD81 expression confers susceptibility to HCV infection in hepatoma cell lines lacking CD81, such as HepG2 cells [31,57,58]. Furthermore, CD81 expression levels have been shown to affect the efficiency of HCV entry [59,60]. Interestingly, a recent study demonstrated modulation of HCV RNA replication depending on CD81 expression . These results suggest multiple and diverse roles of CD81 in the HCV life-cycle.
Various studies identified regions and residues of CD81 involved in the interaction with E2 and the viral particle (Figure 1). Indeed, E2 interacts with the LEL of CD81. E2-CD81 interaction is specific, since E2 does not bind other tetraspanins such as CD9 or CD151 [29,30,31,62,63,64]. Moreover, whereas CD81 LEL plays a direct role in HCV infection by mediating E2 binding, CD81 SEL plays an indirect role by regulating the optimal cell surface expression of LEL . Several other regions of CD81, such as the C-terminal region, transmembrane residues and post-translational modification (e.g., palmitoylation of cysteines in the juxtamembrane domain) have been shown to be important for HCV entry via indirect mechanisms e.g., by mediating oligomerization of CD81, by facilitating interaction with other proteins and by cholesterol partitioning . It is worth noting that residues in transmembrane domains and/or cysteine-mediated palmitoylation seem to exert only moderate inhibitory effects on HCV entry. This indicates that CD81 LEL is the key determinant of viral entry and that additional regions of CD81 only enhance viral entry.
CD81 expression on the cell surface is regulated by the membrane lipid composition. Sphingolipids associate with cholesterol to form lipid rafts and thus are important for plasma membrane organization. It has been shown that enrichment of ceramide in the plasma membrane induces internalization of CD81, thereby inhibiting HCV entry . The cholesterol content of the plasma membrane is also important for HCV entry. It has been demonstrated that depletion of cholesterol—that is required for maintaining membrane fluidity—from cellular membranes inhibits HCV infection. This correlates with decreased amounts of CD81 at the cell surface since CD81 physically interacts with cholesterol [5,68]. Furthermore, it has been shown that the dynamic nature of CD81 and its lateral diffusion is dependent on cell polarization and correlate with HCV infection . In addition, recent data suggest a role of CD81 trafficking in the HCV entry process . Indeed, CD81 engagement with HCV or a CD81−specific antibody promotes clathrin-dependent internalization of CD81. Interestingly, the CD81−specific antibody also appears to neutralize HCV after its internalization, suggesting that intracellular CD81 plays a role in HCV infection .
2.2. The Tetraspanin Complex Formation during HCV Entry and Downstream Signaling Pathways
HCV relies on multiple host factors to gain entry into hepatocytes (reviewed in ). This includes two molecules of the tetraspanin superfamily, namely CD81 and CD63. Interestingly, both tetraspanins have been shown to interact with the viral envelope glycoprotein E2, and may thus directly interact with HCV during the viral entry process [29,78]. While CD81 does not bind any known endogenous ligand nor possess an internalization motif, binding of HCV glycoprotein E2 or CD81-specific antibodies to CD81 has been shown to activate GTPases Rac, Rho and Cdc42 as well as the MAPK signaling pathways [75,76]. These cellular events could regulate HCV interactions with its co−receptors and establish viral entry into target cell. In addition, CD63 is involved in clathrin−dependent endocytosis and vesicle trafficking to lysosomes, suggesting that CD63 may facilitate HCV uptake. Furthermore, while CD81 and CD63 have been involved in TEM formation , it is not yet known whether they interact with each other in hepatocytes.
Besides the potential direct effect in HCV envelope glycoprotein binding and subsequent downstream events described above, CD81 has also been shown to contribute to HCV entry by forming a co-receptor complex through its interaction with other proteins. A major breakthrough was the identification of the CD81-CLDN1 co-receptor complex [80,81]. Noteworthy, while there is no physiological role for this complex known to date, the association of CD81 to CLDN1 is a mandatory step of the HCV entry process. CLDN1 is an integral transmembrane protein of 25 kDa with membrane topology similar to CD81 . However, it is not classified as a classical tetraspanin because of the lack of four cysteines and a CCG motif in the extracellular loop two, one of the defining features of tetraspanins. It has been demonstrated that CLDN1 is an essential host cell factor for HCV entry as cells lacking CLDN1 are resistant to HCV . However, in contrast to CD81, CLDN1 is not seen as a classical HCV receptor as it does not directly bind to soluble HCV glycoprotein E2, a key viral protein involved in HCV entry. Neither CD81 nor CLDN1 appear to bind infectious viral particles [83,84], probably due to the masking of the viral envelope by host-derived lipoproteins, however, a recent study reported that E1E2 complexes are able to interact with CLDN1 . These data suggest that CLDN1, like CD81, may contribute to HCV envelope glycoprotein binding, but that both proteins recognize distinct parts of the viral envelope. While predominantly expressed at the tight junction (TJ), CLDN1 also localizes on the basolateral membrane of hepatocytes. Noteworthy, this pool of CLDN1 outside of the TJ co-localizes with CD81 and allows the formation of the CD81−CLDN1 co-receptor complex that is essential for HCV entry [80,81,84]. Interestingly, CLDN1 co-localizes not only with CD81 at the plasma membrane, but also with SR-BI, another important HCV entry factor, suggesting that these HCV entry factors may be part of a larger membrane complex important for viral entry [42,86,87].
A genome-wide host kinase RNAi screen demonstrated an important regulatory role of kinases for HCV entry and infection . Several kinases have been implicated in CLDN1 cellular localization, relocation and CD81-CLDN1 co-receptor complex formation including protein kinase A (PKA)  and receptor tyrosine kinases (RTKs) . Inhibition of EGFR kinase activity by erlotinib or silencing EGFR expression reduces CD81 association to CLDN1 at the cell surface . This highlights a role of EGFR signaling in the formation of the CD81-CLDN1 co-receptor complex and subsequent HCV entry. While EGFR is known to activate many downstream signals in various cell types, it has been demonstrated that EGFR predominantly activates MAPK signaling in hepatocytes . Indeed, HRas GTPase, a molecular switch for the activation of the MAPK pathway, was identified as a cellular transducer of RTK signals required for HCV entry . A differential proteomic approach allowed to identify HRas as well as CLDN1, SR-BI, integrin beta 1 (ITGB1) and Rap2B as specifically CD81 TEM-associated proteins . Given that all these host factors play a role in HCV entry, these data indicate the existence of a functional membrane network of proteins involved in viral entry . As HRas signaling has been demonstrated to modulate lateral membrane diffusion of CD81 which allows assembly of the tetraspanin receptor complex subsequently mediating HCV entry , HRas appears at the crossroad of interplay between EGFR signaling and the CD81 receptor complex (Figure 2). Taken together, these findings suggest that HCV may manipulate RTK signaling to promote its propagation. Indeed, it has been shown that virus engagement to CD81 activates phosphatidylinositol-3-kinase (PI3K)/Akt pathway  and EGFR that could contribute to virus internalization . This indicates that HCV actively influences the composition of CD81 TEMs via signaling events in order to promote its own entry into target cells. As CD81 has also been shown to be important for influenza entry and HRas has been shown to play a role in influenza  and measles virus  entry, perturbation of TEMs may represent a novel concept for the development of antiviral strategies that may be effective against several pathogens using the same machinery.
4. Conclusions and Perspectives
TEMs play a role in membrane compartmentalization leading to coupling and/or regulating molecular machinery and signaling pathways in a tissue specific manner. The tetraspanin CD81 is not only a key HCV entry factor, but also a molecular organizer of plasma membrane microdomains that contain the molecular machinery used by HCV. Signal transduction through associated tetraspanins and partner proteins likely induce actin remodeling allowing lateral movement of CD81, which appears to be required for HCV entry. This suggests a cooperative action of HCV entry factors and molecules required for vesicle formation and trafficking, leading to compartmentalization of entry factors in TEMs. Moreover, recent studies have also highlighted a central role of CD81 TEMs and virus-induced host cell signaling for entry of HCV [42,90]. Taken together, these data support a model where CD81 complexes, activated either by the virus itself or by RTK signaling, provide a functional link between CD81 trafficking and CD81-CLDN1 association that are prerequisites of HCV entry and highlight a crucial role of TEM “platforms” in the HCV entry process. These findings suggest that CD81 TEMs are highly relevant for pathogen entry such as HCV. Additionally, as CD81 mediated TEMs are required by other viruses, they present potential targets for novel broad spectrum antivirals.
We thank Olga Koutsopoulos (INSERM U1110) for critical reading of the manuscript. The authors work is supported by the European Union (ERC-2008-AdG-233130-HEPCENT, Interreg IV FEDER-Hepato-Regio-Net 2012 and FP7 HEPAMAB GAN 305600), the Agence Nationale de Recherches sur le SIDA et les hépatites virales (ANRS) (2012/239, 2013/081, 2013/249), the Direction Générale de l'Offre de Soins (A12027MS), Inserm, University of Strasbourg and ARC (TheraHCC). This work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS and benefits from a funding from the state managed by the French National Research Agency as part of the Investments for the future program.
LZ, RGT, MBZ and TFB prepared the manuscript. FX and JL designed illustrations. LZ, RGT, MBZ, FX, CS, JL and TFB edited the manuscript. MBZ and TFB supervised the work. LZ and RGT contributed equally.
Conflicts of Interest
The authors declare no conflict of interest. Inserm, the University of Strasbourg and Aldevron/Genovac have filed patent applications on monoclonal antibodies targeting host factors and inhibiting HCV infection and kinases as antiviral targets.
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