Disease relevance of CD81

• Like CD81, several tetraspanins are involved in cell adhesion, motility, and metastasis, as well as cell activation and signal transduction [1].
• HTLV-1 MA also interacted with the inner loop of CD81 [2].
• To further characterize the major proteins present in a typical TM4SF protein complex, we raised monoclonal antibodies against proteins co-immunoprecipitated with CD81 from MDA-MB-435 breast cancer cells [3].
• CD81 is required for hepatitis C virus glycoprotein-mediated viral infection [4].
• CD81 is required for HIV-HCV pseudotype infection since (i) a monoclonal antibody specific for CD81 inhibited infection of susceptible target cells and (ii) silencing of CD81 expression in Huh-7.5 hepatoma cells by small interfering RNAs inhibited HIV-HCV pseudotype infection [4].

Psychiatry related information on CD81

• A correlation between binding to CD81 and species permissiveness to HCV infection has also been reported [5].
• Furthermore, silencing endogenous CD81 in vivo resulted in a significant decrease in locomotor activity over controls, again suppressing cocaine-induced behaviour [6].
• Alcohol consumption had no effect on expression of HCV putative receptors in PBMC, except for CD81, which was upregulated on monocytes in group 2 [7].
• We designed a clinical study to evaluate the impact of alcohol abuse on both viral load and expression of low-density lipoprotein receptor (LDLR) and CD81 expression [7].

High impact information on CD81

• CD81 can also affect cognate B-T cell interactions because anti-CD81 increases IL-4 synthesis by T cells responding to antigen presented by B cells but not by monocytes [1].
• However, CD81-deficient mice express normal numbers and subsets of T cells [1].
• In fetal thymic organ culture, mAb to CD81 block maturation of CD4-CD8- thymocytes, and expression of CD81 on CHO cells endows those cells with the ability to support T cell maturation [1].
• CD81 (TAPA-1): a molecule involved in signal transduction and cell adhesion in the immune system [1].
• The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural to acquired immunity [8].

Chemical compound and disease context of CD81

• CD81 was analyzed by flow cytometry in CD8(+), CD4(+), CD19(+), and CD56(+) lymphocyte subtypes from 20 patients with chronic hepatitis C before, during, and after antiviral treatment with pegylated interferon-alpha (IFN-alpha) and ribavirin [9].

Biological context of CD81

• CD19 and CD21 are B-cell surface molecules that associate with each other and with CD81 and Leu-13 to generate a signal transduction complex that is independent of the antigen receptor [10].
• Transfection of a series of chimeric constructs comprising CD9 and CD81 showed that the major extracellular domain of CD9 is essential for up-regulation [11].
• In addition, the amino acid sequences of these carboxyl regions appeared to show partial homology to CD81, a candidate receptor for HCV, and the binding activity of these carboxyl regions was also comparable with that of CD81 [12].
• Interestingly, antibodies against other tetraspanins expressed in Du145 cells such as CD9, CD81, and CD151 did not block this integrin alpha6-dependent morphogenesis [13].
• Role of complement-binding CD21/CD19/CD81 in enhancing human B cell protection from Fas-mediated apoptosis [14].

Anatomical context of CD81

• Finally, anti-CD9 and anti-CD81 monoclonal antibodies triggered apoptotic degeneration of C2C12 cell myotubes after they were formed [15].
• Ectopic expression of CD9 caused a four- to eightfold increase in RD cell syncytia formation, whereas anti-CD9 and anti-CD81 antibodies markedly delayed RD syncytia formation [15].
• In summary, TM4SF proteins such as CD9 and CD81 appear to promote muscle cell fusion and support myotube maintenance [15].
• Enhanced signaling is due in part to the ability of the CD19/CD21/CD81 complex to stabilize the BCR in sphingolipid- and cholesterol-rich membrane microdomains termed lipid rafts [16].
• Transmembrane-4-superfamily proteins CD151 and CD81 associate with alpha 3 beta 1 integrin, and selectively contribute to alpha 3 beta 1-dependent neurite outgrowth [17].

Associations of CD81 with chemical compounds

• Anti-alpha 4 integrin mAb also coprecipitated CD81 from the alpha 4 beta 7-positive B cell line RPMI 8866 [18].
• We have examined the role of CD81 in HCV glycoprotein-dependent entry by using a recently developed retroviral pseudotyping system [4].
• On mAb binding, CD38 translocates to the membrane lipid microdomains, as shown by a colocalization with the GM1 ganglioside and with CD81, a raft-resident protein [19].
• We have generated a series of CD81 cysteine mutants to identify palmitoylated intracellular motifs of CD81, and reveal palmitoylation on the N- and C-terminal tails as well as the intracellular loop between transmembrane domains 2 and 3 [20].
• Here, we show that CD81 clustering stimulates ERK/MAPKinase activity and tyrosine phosphorylation of the adapter protein Shc in Huh7 cancer cells [21].

Physical interactions of CD81

• Here, we examine whether coligation of the B cell Ag receptor (BCR) with the complement (C3)-binding CD21/CD19/CD81 costimulatory complex can enhance the escape of human B cells from Fas-induced death [14].
• CD9P-1 was also shown to form separate complexes with CD81 and with an unidentified 175-kDa molecule [22].
• Hepatitis C virus (HCV) or HCV-low-density lipoprotein (LDL) complexes interact with the LDL receptor (LDLr) and the HCV envelope glycoprotein E2 interacts with CD81 in vitro [23].
• Cross-linking CD81 is also shown to be costimulatory with signaling through the TCR/CD3 complex inducing interleukin 2-dependent thymocyte proliferation [24].

Co-localisations of CD81

• Also, two-color immunofluorescence showed that NAG-2 was co-localized with CD81 on the surface of spread HT1080 cells [3].

Regulatory relationships of CD81

• Finally, we found that the binding of p56lck to CD4 strongly inhibited its association with CD81 and CD82 [25].
• The low-density lipoprotein receptor (LDLR) has been proposed to promote hepatitis C virus endocytosis and the cell membrane protein CD81 may also promote HCV host cell entry [26].
• Videomicroscopy studies with APC or T cells transiently expressing CD81-green fluorescent protein (GFP) revealed that in both cells CD81 redistributed toward the central supramolecular activation complex [27].
• E2-CD81 interaction on B cells triggered the enhanced expression of activation-induced cytidine deaminase (AID) and also stimulated the production of tumor necrosis factor alpha [28].
• E2-CD81 interaction stimulates translocation of PKC-beta to lipid rafts, thereby preventing its association with the centrosome and microtubule cytoskeleton, which is crucial to the process of T-cell migration [29].

Other interactions of CD81

• In nonstringent detergent, NAG-2 protein was co-immunoprecipitated with other TM4SF members (CD9 and CD81) and integrins (alpha3beta1 and alpha6beta1) [3].
• Thus, association of HTLV-1 Gag with tetraspanin-enriched microdomains is mediated by the inner loops of CD81 and CD82 [2].
• Also, cross-linking experiments established that alpha 3 beta 1/CD81, alpha 3 beta 1/CD9, and alpha 3 beta 1/CD63 associations occur on the surface of intact cells and suggested that a critical interaction site is located within extracellular domains [30].
• The palmitoylation of CD9 did not influence the partition in detergent-resistant membranes but contributed to the interaction with CD81 and CD53 [31].
• Here, we investigated whether altered CCR5 expression in hepatitis C results from interactions of CD81 with the HCV E2 protein [32].

Analytical, diagnostic and therapeutic context of CD81

• As shown by confocal microscopy, CD81 and CD82 colocalized with alpha 4 beta 1 in cell surface clusters [18].
• Finally, we demonstrate that ligation of CD81 by E2661 induced aggregation of lymphoid cells and inhibited B-cell proliferation, demonstrating that E2 interaction with CD81 can modulate cell function [33].
• CD81 has been described as a putative receptor for hepatitis C virus (HCV); however, its role in HCV cell entry has not been characterized due to the lack of an efficient cell culture system [4].
• In contrast, reciprocal immunoprecipitations from various cell lines demonstrated that two other tetraspans, CD81 and CD151, formed complexes with integrins not disrupted by digitonin [34].
• Using electron microscopy, we confirm that HIV-1 accumulates in intracellular vacuoles that contain CD81 positive internal membranes but overlaps only partially with CD63 [35].

References