JOURNAL OF VIROLOGY, Sept. 2005, p. 1083910851 Vol. 79, No. 170022-538X/05/$08.000 doi:10.1128/JVI.79.17.1083910851.2005Copyright 2005, American Society for Microbiology. All Rights Reserved.
Tetraspanins in Viral Infections: a Fundamental Role in Viral Biology?F. Martin,1 D. M. Roth,2,3 D. A. Jans,2 C. W. Pouton,3 L. J. Partridge,4 P. N. Monk,1 and
G. W. Moseley2*Academic Neurology Unit, Division of Genomic Medicine, University of Sheffield, Sheffield, United Kingdom,1 Department ofBiochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia,2 Victorian College of Pharmacy,
Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia,3 and Department of Molecular Biology andBiotechnology, University of Sheffield, Sheffield, United Kingdom4
The tetraspanins are a broadly expressed superfamily oftransmembrane glycoproteins with over 30 members found inhumans and with homologues conserved through distantly re-lated species, including insects, sponges, and fungi. Membersof this family appear to form large integrated signaling com-plexes or tetraspanin-enriched microdomains (TEMs) by theirassociation with a variety of transmembrane and intracellularsignaling/cytoskeletal proteins (49). These interactions link tet-raspanins to an array of physiological functions and, in conse-quence, to numerous endogenous pathologies, including can-cer development and inherited disorders (Table 1).
Tetraspanins are also known to have roles in the pathologyof infectious diseases such as diphtheria, malaria, and numer-ous viral infections (Table 1). The literature currently indicatesthat specific tetraspanin family members are selectively asso-ciated with specific viruses and affect multiple stages of infec-tivity, from initial cellular attachment to syncytium formationand viral particle release. Thus, the relationship of tetraspaninswith viruses appears to be particularly complex.
Here, we will consider this data in the context of recentdevelopments in tetraspanin biology, particularly in our under-standing of the architecture and function of TEMs. With thebenefit of recent insights into tetraspanin function in cell fu-sion events and intracellular trafficking, we discuss commonfeatures of tetraspanin/viral associations which indicate a fun-damental role for TEMs in a number of viral infections. Wewill also consider the existing therapeutic strategies for humanimmunodeficiency virus (HIV), hepatitis C virus (HCV), andhuman T-cell lymphotropic virus type 1 (HTLV-1), focusing onthe potential therapeutic value of targeting TEMs, using pep-tide reagents based on tetraspanin extracellular regions.
THE TETRASPANIN SUPERFAMILY
Structural features of the tetraspanin superfamily. Tet-raspanins are type III membrane glycoproteins which span theplasma membrane four times, producing two extracellularloops and short intracellular regions (Fig. 1). A defining struc-
tural signature of the superfamily is the tetraspanin fold ofthe larger extracellular loop (LEL). In this region, disulfidebonding of four absolutely conserved cysteines forms a subloopstructure containing a region which is hypervariable betweenfamily members and between species homologues of the sametetraspanin (Fig. 1) (81, 142). The cysteines are present inthree variously conserved motifs (CysCysGly, ProXSerCys[where X any amino acid], and GluGlyCys) (Fig. 1), whereinthe flexibility and constraint imparted by the conserved Glyresidue in CysCysGly and by Pro in ProXSerCys contribute tosubloop formation (68). Many members of the tetraspaninfamily have one or two additional pairs of Cys residues in thetetraspanin fold region, potentially allowing the formation ofcomplex subloop structures. The region of the LEL outside ofthis subloop shows greater structural conservation, formingthree -helices which not only form a structural platform topresent the tetraspanin fold but may also contribute indepen-dently to tetraspanin function (see below) (68, 152).
Conservation of the canonical LEL Cys, Gly, and otherresidues, including charged transmembrane amino-acids, dis-tinguishes members of the tetraspanin superfamily properfrom other tetraspan proteins (168). Modification of tet-raspanins includes O- and N-linked glycosylation. N glycosyl-ation sites are largely located in the LEL, and glycosylation hasbeen shown to regulate specific tetraspanin functions (111). Nglycosylation is generally assumed to occur at classical AsnXSer/Thr sites, but the LELs of some tetraspanins, includingCD9 and CD81, contain the rarer AsnXCys N-glycosylationmotif (138) which, interestingly, incorporates canonical cys-teines. Mutation of the only AsnXSer sites in CD9 does notprevent N glycosylation, indicating that the AsnXCys site maybe utilized in some cases (G. W. Moseley, L. J. Partridge, andP. N. Monk, unpublished data). Palmitoylation of tetraspaninshas also been shown to be functionally significant, as it appearsto participate in the formation of heterotetraspanin associa-tions (14) and to regulate association with lipid rafts (seebelow) (16).
Tetraspanin-enriched microdomains. Tetraspanins affectmultiple events in vitro, including cellular signaling, migration,adhesion, fusion, cytoskeletal reorganization, and prolifera-tion, which appear relevant to altered expression patterns seenduring cellular activation, differentiation, proliferation, andmalignant transformation in vivo (reviewed in references 87and 168). Tetraspanins are expressed by all mammalian tissues,
* Corresponding author. Mailing address: Nuclear Signalling Labo-ratory, Department of Biochemistry and Molecular Biology, MonashUniversity, Building 13D, Monash, Victoria 3080, Australia. Phone:61-3-99051220. Fax: 61-3-99053726. E-mail: email@example.com.
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although the complement of family members expressed is tis-sue specific (Table 1). It is unsurprising, therefore, that tet-raspanin functions have been identified in an array of celltypes, including platelets, epithelial/endothelial cells, musclecells, and photoreceptor cells and cells of the immune, centralnervous, and reproductive systems (87, 99). The basis for thisbroad functionality appears to be the capacity of tetraspaninsto form multiple intermolecular interactions with a restrictedbut varied complement of transmembrane and intracellularmolecules (Fig. 2).
Tetraspanins have no intrinsic enzymatic activity or typicalsignaling motifs (with the exception of the recently identified14-3-3 binding motif in CD81 ), so it has been predicted thatthey act primarily as novel adapter proteins, facilitating the inter-action of associated molecules in tetraspanin signaling networks
(tetraspanin web  or TEMs ). The evidence that phys-ical associations of tetraspanins are functionally relevant iscompelling. For example, in vitro modulation of tetraspan-ins on cell adhesion/migration or growth have been shown tobe dependent on tetraspanin-associated integrins (76, 93,143) and progrowth factors (75, 144). Similar observationshave been made in vivo in tetraspanin-null animals (167).
Analogies have been drawn between TEMs and lipid rafts.In the latter, protein-protein interactions are facilitated byassociation with membrane regions enriched for cholesteroland glycosphingolipids (149). In either lipid rafts or TEMs theassociated proteins are believed to form large, integrated sig-naling platforms. Although TEMs and lipid rafts exist as sep-arate entities, they have been shown to interact physically andfunctionally (17, 27).
TABLE 1. Members of the tetraspanin superfamily with reported links to pathologiesa
Tetraspanin Alternative name Tissue distribution Pathological link Reference
CD9 TM4SF2, DRAP-27, MRP, MIC3,p24
Platelets, early B cells, activated anddifferentiating B cells, activated Tcells, eosinophils, basophils,endothelial cells, megakaryocytes,epithelia, dendritic cells, brainand peripheral nerves, fibroblasts,lung, kidney, liver, vascularsmooth muscle, skeletal muscle,keratinocytes
Expressed on leukemias,melanomas, and cancers ofbreast, lung, colon, and pancreas;modulates affinity of diphtheriatoxin receptor (pro-HB EGF);linked with FIV, HIV, and CDV(see text)
CD63 TM4SF1, MEL1, ME491,granulophysin, LAMP3, OMA81H,MLA1
Wide lymphoid and nonlymphoiddistribution, including platelets,neutrophils, monocytes,macrophages, dendritic cells,endothelia, megakaryocytes,epithelia, fibroblasts, lung, kidney,liver, smooth muscle, skeletalmuscle, peripheral nerves,pancreas, and cardiac muscle
Expression correlated withmelanoma progression;b linkedwith HIV infection (see text)
CD81 TM4SF10, TAPA-1 Broad expression on nonlymphoidtissues and on lymphocytes,thymocytes, follicular dendriticcells, eosinophils, monocytes, andepithelia
Potential roles in HCV infection(see text); involved ininternalization of Plasmodiumfalciparum and P. yoelii
CD82 TM4SF11, Kangail, KAI1, SDT6,R2 Ag
B and T cells, NK cells, monocytes,granulocytes, and platelets andvarious nonhemopoietic cells
Expression linked to prostate, lung,colon, hepatoma, and breastcancers; involved in HTLV-1infection (see text)
CD151 TM4SF32, PETA3, SFA1, gp27 Endothelial cells, platelets, dendriticcells, megakaryocytes, epithelia,lung, kidney, liver, smooth andskeletal muscles and peripheralnerves, keratinocytes, pancreas,and cardiac muscle
Upregulated in HTLV-1 infection;expressed in colon and lungcancers
CD231 TM4SF27, A15, TALLA1, TM4-2b Heart, brain, lung, liver, skeletalmuscle, kidney, pancreas, andimmature T cells.
Expressed in neuroblastomas andleukemias; ge