The journal Cancers recently published a paper titled "Targeting of Tetraspanin CD81 with Monoclonal Antibodies and Small Molecules to Combat Cancers and Viral Diseases" [1]. This paper highlights CD81 as a crucial target in treating cancer and viral infections, detailing its role in cancer development, metastasis, and as a co-receptor for viruses like HCV and HIV. The study focuses on using monoclonal antibodies and small molecules to disrupt CD81's function, showing promise in combating related disease conditions by blocking its interactions with its partners. Additionally, CD81, a well-known marker in exosomes, shows potential for drug delivery and disease research, especially in cancer studies. Let's explore further about CD81, a tetraspanin protein with significant implications across various disease researches!
4. Prospects for Clinical Research on CD81
5. CUSABIO CD81 Recombinant Proteins & Antibodies for Research Use
CD81 (also called Tetraspanin-Associated Protein 1, TAPA-1), was first discovered as the receptor for HCV-infected cells during a screening for antibodies inhibiting B-lymphoblastoma growth. It belongs to the tetraspanin superfamily (Tetraspanins/TM4SF) (click to learn more about "What is the TM4SF family"). CD81 comprises four transmembrane regions, two cytoplasmic regions (N-terminal and C-terminal), and an extracellular domain (EC). The EC consists of EC1 (28 amino acid residues) between TM1 and TM2, maintaining CD81's surface conformation, and EC2 (80 residues) between TM3 and TM4. EC2 forms a larger loop (LEL) critical for CD81's species specificity and binding to the hepatitis C virus (HCV) protein E2. Within the LEL, the formation of two disulfide bonds among four cysteine residues is crucial for HCV E2's recognition of CD81 (Figure 1) [1-2].
CD81, found in many tissue cells but not in red blood cells or platelets, is essential for cell functions like growth, development, protein transport, and immune responses. It acts as a channel protein, impacting infections such as Hepatitis C Virus (HCV) and Plasmodium falciparum by binding to specific partner proteins from the tetraspanin family. As part of the tetraspanin superfamily (including CD9, CD63, CD81, and CD82), these proteins signal potential disease-related changes. CD81, alongside other transmembrane proteins, contributes to the network involved in sperm-egg interactions, vital for fertility. Notably, the CD81 gene resides in the oncogene region of tumor cells, influencing tumor growth, metastasis, and various biological processes [3-5].
Figure 1. The structure of CD81 [2]
CD81 forms crucial partnerships with various molecules, facilitating essential cell interactions, signaling, and molecular pathway regulation. For instance, in B cells, it binds with proteins like CD21, CD19, and Leu13 to activate B cells. In viral studies, CD81's large loop (CD81-LEL) binds with HCV's E2 glycoprotein, aiding efficient HCV genome replication. Additionally, CD81 pairs with CLDN-1 to create the CD81-CLDN-1 receptor complex, crucial for HCV's initial binding and invasion into host cells. As a significant receptor for HCV, CD81 guides viral particles into cells and potentially influences virus-cell signaling (Figure 2) [6-7].
Figure 2. The mechanisms associated with CD81 and viral infection [6]
The CD81 protein was discovered to bind Integrin a4β1 in T cells like Molt4 and Jurkat cells, while its β1 Integrin family interacts with CD53, CD63, and CD82 proteins. Additionally, CD81 was observed binding to CD82 in T-cell lines. When CD81 antibodies were immobilized, they induced alterations in T-cell shape by forming cellular protrusions. Treating rat astrocytes with CD81 monoclonal antibodies also increased cell protrusion. Similar effects were seen with T cells and CD82 monoclonal antibodies, which were inhibited by cytochalasin D and colchicine. These findings indicate that both CD81 and CD82 proteins play a role in modifying cell morphology [8-10].
CD81 forms complexes with integrins and other proteins on the cell membrane, crucial for signaling and influencing the function of cellular signaling systems. In non-small cell lung cancer (NSCLC) cells, CD81 overexpression binds to ITGB1, a part of the integrin receptor family. When CD81, ITGB1, and ITGA3 are co-overexpressed, CD81 promotes the binding of ITGB1 to ITGA3, activating Integrin. This activation triggers pathways like AKT and ERK1/2, enhancing NSCLC cell proliferation and migration. This underscores CD81's significant role in tumor progression and provides insights for future cancer research (Figure 3) [11-13].
Figure 3. CD81 and tumor-related mechanisms [13]
Viral infection relies on the close connection between viral glycoproteins and specific cell surface receptor proteins, a crucial step in the infection process. Hepatitis C Virus (HCV) infection in humans leads to chronic hepatitis, hepatocellular carcinoma, and cirrhosis. CD81, a key cell membrane glycoprotein, plays a vital role in HCV infection. Antibodies against CD81 can hinder various HCV infections, while reducing CD81 in liver cancer cells using small RNA prevents HCV infection. As the primary receptor for HCV, CD81 not only binds directly to the HCV glycoprotein E2 but also forms a complex with other HCV co-receptors like Claudin-1, Claudin-6, Claudin-9, Occludin, and SR-BI. This complex facilitates subsequent HCV engulfment [14-18].
CD81 is pivotal not just in infection and immunity but also in tumorigenesis and metastasis. In many tumors like B-cell lymphoma and various malignant cells, CD81 levels surpass those in normal cells. In patients, CD15 and CD81 foster tumorigenesis, whereas CD63 and CD82 inhibit it [19-20]. However, CD81's role varies across different cancers. For instance, in hepatocellular carcinoma and gastric cancer cells, lower CD81 levels correlate with higher metastatic potential [21, 19, 22]. Conversely, melanoma cells exhibit increased migration and metastasis with higher CD81 expression [23]. Through an Akt-dependent Sp1 signaling pathway, CD81 induces MT1-MMP expression in melanoma, amplifying cell motility and metastasis [23-24]. Moreover, CD81 deficiency significantly impairs regulatory T cells and myeloid-derived suppressor cells [25].
Many studies show that CD81, a molecule on exosomes, is involved in various diseases. For example, exosomes from human mesenchymal stem cells (hUCMSCs-Exo) containing CD9, CD81, and TSG101 affect blood vessel function [26]. Additionally, in people with severe depression, exosomes from astrocytes have higher levels of CD81, suggesting its role in the disease [27]. Exosomes from people with hypertension also contain CD63, CD9, and CD81, indicating their potential involvement in the disease process [28].
Studies on pancreatic cysts show that cyst fluid contains a variety of extracellular vesicles (EVs) with different CD63 and CD81 characteristics. Analyzing these EVs from cyst fluid may help to more accurately classify patients with these cysts [29]. In cervical cancer research, analyzing exosomes using various techniques provides information about CD63, CD81, TSC101, Bcl-2, Bax, Caspase 3, and RSF1, which can help to understand the disease's development [30]. Furthermore, exosomes from cancer-associated fibroblasts (CAFs) containing CD63, CD81, and TSG101 contribute to tumor progression by delivering molecules [31]. Changes in CD81 levels in exosomes provide insights into specific diseases, making CD81 a promising target for studying conditions such as microvascular dysfunction, depression, hypertension, pancreatic cysts, and tumor progression.
CD81, a member of the transmembrane 4 superfamily, also known as the tetraspanin family, shows promise for treating HCV infection and cancer. Its large extracellular loop (EC2) is a major protein interaction hub, making it a compelling drug target. Research on CD81-targeting monoclonal antibodies (mAbs) has focused on understanding CD81's expression and function, particularly in viral infections and cancer metastasis. CD81 is a receptor for HCV entry, suggesting potential for CD81-targeted cell entry inhibitors to treat HCV. CD81 also interacts with cancer-associated proteins (e.g. CD19, CD44, and EWI-2 etc.), suggesting a role in cancer cell proliferation, migration, and metastasis. The success of other Tetraspanins/TM4SF proteins in drug discovery for cancer and other diseases, such as CD3,CD20,CD37,CCR8,CD40L,CD48/NKG2D ligand, which further supports CD81 as a promising therapeutic target. All in all, CD81-based drugs are expected to enter clinical development soon, offering a novel approach to treating these diseases.
CD81, a tetraspanin receptor, vital for Hepatitis C Virus (HCV) entry and cancer, has diverse disease roles. It comprises crucial regions for HCV binding, affecting cell growth, immunity, and pathogen entry. In cancer, it boosts metastasis (e.g., melanoma) or inhibits it (e.g., hepatocellular carcinoma). CD81 on exosomes links to diseases (e.g., depression, hypertension, cancer). It aids viral entry, alters cell shape, and impacts tumor growth. Ongoing studies see CD81 as a drug target for various diseases research.
To fully support researchers and pharmaceutical companies in their research on CD81 in hepatitis C virus and cancer, CUSABIO has launched CD81 active protein (CSB-MP004960HU) and antibody (CSB-RA004960A0HU; CSB-RA004960MA1HU) products to aid your research in the mechanism of CD81 or the exploration of its potential clinical value.
CUSABIO CD81 Protein
Recombinant Human CD81 antigen (CD81), partial (Active) Code: CSB-MP004960HUd7
The high purity is greater than 95% as determined by SDS-PAGE.
Immobilized Human CD81 at 2μg/mL can bind Anti-CD81 recombinant antibody (CSB-RA004960MA1HU). The EC50 is 4.166-5.578 ng/mL
References
[1] Bailly, Christian, and Xavier Thuru. "Targeting of Tetraspanin CD81 with Monoclonal Antibodies and Small Molecules to Combat Cancers and Viral Diseases." Cancers 15.7 (2023): 2186.
[2] Fénéant, Lucie, Shoshana Levy, and Laurence Cocquerel. "CD81 and hepatitis C virus (HCV) infection." Viruses 6.2 (2014): 535-572.
[3] Koutsoudakis, George, et al. "The level of CD81 cell surface expression is a key determinant for productive entry of hepatitis C virus into host cells." Journal of virology 81.2 (2007): 588-598.
[4] Akazawa, Daisuke, et al. "CD81 expression is important for the permissiveness of Huh7 cell clones for heterogeneous hepatitis C virus infection." Journal of virology 81.10 (2007): 5036-5045.
[5] Inoue, G. A. K. U., N. O. R. I. O. Horiike, and M. O. R. I. K. A. Z. U. Onji. "The CD81 expression in liver in hepatocellular carcinoma." International journal of molecular medicine 7.1 (2001): 67-138.
[6] Bailly, Christian, and Xavier Thuru. "Targeting of Tetraspanin CD81 with Monoclonal Antibodies and Small Molecules to Combat Cancers and Viral Diseases." Cancers 15.7 (2023): 2186.
[7] Wünschmann, Sabina, et al. "Characterization of hepatitis C virus (HCV) and HCV E2 interactions with CD81 and the low-density lipoprotein receptor." Journal of virology 74.21 (2000): 10055-10062.
[8] Todros-Dawda, Izabela, et al. "The tetraspanin CD53 modulates responses from activating NK cell receptors, promoting LFA-1 activation and dampening NK cell effector functions." PLoS One 9.5 (2014): e97844.
[9] CHAN12, BOSCO MC, et al. "Integrin α2βΐ on rat myeloma cells modulates interaction of α4β1 integrin with vascular cell adhesion molecule-1 but not hbronectin." Cells, Proteins and Materials: Festschrift in Honor of the 65th Birthday of Dr. John L. Brash (2003): 119.
[10] Tippett, Emma, et al. "Characterization of tetraspanins CD9, CD53, CD63, and CD81 in monocytes and macrophages in HIV-1 infection." Journal of Leukocyte Biology 93.6 (2013): 913-920.
[11] Rubio, Karla, et al. "Extracellular vesicles induce aggressive lung cancer via non-canonical integrin-EGFR-KRAS signaling." bioRxiv (2022): 2022-08.
[12] Rubio, Karla, et al. "Non-canonical integrin signaling activates EGFR and RAS-MAPK-ERK signaling in small cell lung cancer." Theranostics 13.8 (2023): 2384.
[13] Guo Wenjie. Molecular mechanism of HHEX regulating integrin signaling pathway in lung cancer cells through CD81 [D]. Shandong University, 2021.
[14] Meertens, Laurent, et al. "The tight junction proteins claudin-1,-6, and-9 are entry cofactors for hepatitis C virus." Journal of virology 82.7 (2008): 3555-3560.
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[17] Harris, Helen J., et al. "CD81 and claudin 1 coreceptor association: role in hepatitis C virus entry." Journal of virology 82.10 (2008): 5007-5020.
[18] Fofana, Isabel, et al. "Functional analysis of claudin-6 and claudin-9 as entry factors for hepatitis C virus infection of human hepatocytes by using monoclonal antibodies." Journal of virology 87.18 (2013): 10405-10410.
[19] Vences-Catalán, Felipe, et al. "CD81 as a tumor target." Biochemical Society Transactions 45.2 (2017): 531-535.
[20] Belov, Larissa, et al. "Extensive surface protein profiles of extracellular vesicles from cancer cells may provide diagnostic signatures from blood samples." Journal of extracellular vesicles 5.1 (2016): 25355.
[21] Li, Yandong, et al. "KLF4-mediated upregulation of CD9 and CD81 suppresses hepatocellular carcinoma development via JNK signaling." Cell death & disease 11.4 (2020): 299.
[22] Yoo, Tae-Hyoung, et al. "CD81 is a candidate tumor suppressor gene in human gastric cancer." Cellular Oncology 36 (2013): 141-153.
[23] Hong, In-Kee, et al. "The tetraspanin CD81 protein increases melanoma cell motility by up-regulating metalloproteinase MT1-MMP expression through the pro-oncogenic Akt-dependent Sp1 activation signaling pathways." Journal of Biological Chemistry 289.22 (2014): 15691-15704.
[24] Hong, In-Kee, et al. "Tetraspanin CD81/TAPA-1 up-regulates MT1-MMP involved in melanoma cell motility through Akt-dependent Sp1 activation signaling pathways." Cancer Research 70.8_Supplement (2010): 526-526.
[25] Vences-Catalán, Felipe, et al. "Tetraspanin CD81 promotes tumor growth and metastasis by modulating the functions of T regulatory and myeloid-derived suppressor cells." Cancer research 75.21 (2015): 4517-4526.
[26] Fan, Weijian, et al. "Human umbilical cord mesenchymal stem cell-derived exosomes promote microcirculation in aged diabetic mice by TGF-β1 signaling pathway." Diabetology & Metabolic Syndrome 15.1 (2023): 234.
[27] Xie, Xin-hui, et al. "Hyper-inflammation of astrocytes in patients of major depressive disorder: Evidence from serum astrocyte-derived extracellular vesicles." Brain, Behavior, and Immunity 109 (2023): 51-62.
[28] Ahmad, Sarfaraz, et al. "Chymase in Plasma and Urine Extracellular Vesicles: Novel Biomarkers for Primary Hypertension." medRxiv (2023): 2023-11.
[29] Benke, Márton, et al. "MiR-200b categorizes patients into pancreas cystic lesion subgroups with different malignant potential." Scientific Reports 13.1 (2023): 19820.
[30] Chen, Zhilong, et al. "Exosome-delivered circRNA circSYT15 contributes to cisplatin resistance in cervical cancer cells through the miR-503-5p/RSF1 axis." Cell Cycle (2023): 1-18.
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