CD53 is a member of the tetraspanin family of hydrophobic membrane-spanning proteins. Tetraspanins form microdomains on the cell surface that can interact with many different proteins implicated in signaling forming vesicles leading to endosome and exosome formation. CD53 has no known extracellular ligand. The specific function of CD53 has not yet been defined, but CD53 has been shown to modulate cell adhesion, migration, cell proliferation, and survival. Ligation of CD53 with antibodies protects cells from apoptosis; this effect is mediated by phosphorylation and activation of Akt, increased levels of Bcl-Xl, decreasing the amount of Bax, and reducing caspase activation. In mesangial cells, CD53 ligation stimulates the induction of DNA synthesis via the MEK-ERK pathway. CD53 ligation induces calcium mobilization, activation of PKCα, and expression of the inducible nitric oxide synthase gene resulting in increased nitric oxide production. But all these effects may be a consequence of the tetraspanin complex on which CD53 is integrated in specific cell types (Yunta and Lazo 2003b). Exosomes contain additional molecules either on their membrane or in their interior and includes proteins, DNA, and RNA that are released to the circulation. In cancer biology, exosomes thus contribute to their dissemination to other organs in the organism and formation of metastasis.
Most of the functional data associated with CD53 was obtained by CD53 ligation with antibodies. Ligation induces homotypic adhesion in lymphoma cell lines (Cao et al. 1997; Lazo et al. 1997; Yunta and Lazo 2003a). CD53 ligation induces phosphorylation of Akt, increased Bcl-Xl level, reduction of Bax, and activation of caspases, thus protecting cells against apoptosis induced by serum deprivation (Yunta and Lazo 2003a).
CD53 ligation induces a burst of DNA synthesis and initiation of the cell cycle through activation of the MEK-Erk pathway in mesangial cells. However, additional stimuli are required for completion of the cell cycle (Yunta et al. 2003); in the U937 monocyte cell line, CD53 ligation blocked proliferation (Stonehouse et al. 1999). In macrophages, ligation of CD53 induces nitric oxide production through calcium mobilization, activation of PKCα, and expression of the inducible nitric oxide synthase (NOS2) gene (Bosca and Lazo 1994). Calcium mobilization has also been detected in human monocytes and B cells (Olweus et al. 1993). CD53 appears to play an adaptor or scaffold protein that influences adhesion, proliferation, and survival. Additional studies are required to elucidate the precise role for CD53 in these and other cellular processes.
Tetraspanin Web and CD53 Protein Interactions in Plasma Membranes
CD53 directly interacts in these microdomains with several integrins (ITG) containing the β1 chain. The presence or absence of particular integrin α chains varies depending on cell type, but integrin α4β1 coprecipitated with CD53 in several cell lines (Mannion et al. 1996).
Tetraspanin Web and CD53 Interactions with Intracellular Signaling
Several intracellular signaling molecules have been detected as interaction partners of tetraspanins. Among them, PKC can be associated with CD9, CD53, CD81, CD82, and CD151. Although formation and maintenance of tetraspanin-PKC complexes is not dependent on integrins, tetraspanins can act as linker molecules that bring PKC into proximity with specific integrins. The specificity for PKC association probably resides in the cytoplasmic tails or the first two transmembrane domains of tetraspanins, and CD53 has been found to interact with PKCα (PKCA) (Zhang et al. 2001). CD53 crosslinking induces effects mediated by PKCα, such as nitric oxide production by the inducible nitric oxide synthase (NOS2) (Bosca and Lazo 1994), and homotypic cell adhesion in a B-cell lymphoma (Lazo et al. 1997). Also CD53, CD21, CD19, CD81, and CD82 interact with γ-glutamyl transpeptidase (GGT7), a membrane protein involved in recycling extracellular glutathione and regulation of intracellular redox potential (Nichols et al. 1998). This might be relevant for cell sensitivity to radiation mediated, which is affected by the redox state. CD53 is overexpressed 20–50-fold in murine B cells that are resistant to radiotherapy and apoptosis (Voehringer et al. 2000). CD53 coprecipitates with GGT in lymphocytes from patients with rheumatoid arthritis that are also resistant to apoptosis (Pedersen-Lane et al. 2007). CD53 can protect cells from apoptosis by inducing AKT survival signals (Yunta and Lazo 2003a). CD53, CD9, and CD81 have been detected in budding HIV-1 particles in infected macrophages (Deneka et al. 2007).
CD53 Gene Expression and Regulation
Human CD53 expression is restricted to normal B cells during B-cell development (Barrena et al. 2005b). The promoter of the human CD53 gene contains two sites that are recognized by Sp1 and ets1 transcription factors. These sites are essential for its expression in different cell types. Other transcription factors play different roles, in some are activators and in other repressors (Hernandez-Torres et al. 2001). 4BP4 is an activator in erythroleukemic cells and inhibitor in B and T lymphoma cells. Elk-1 activates in T-cell lymphomas and is an inhibitor in B-cell lymphomas. PuF and GATA1 only inhibits in B-cell lymphomas. Thus within the CD53 proximal upstream promoter, some sequences recognized by transcription factors have a different role and in that way contribute to cell-specific expression (Hernandez-Torres et al. 2001). Other transcription factors regulating CD53 expression are the B cell factor (EBF-1), which is required for B cell differentiation (Mansson et al. 2007), and 1,25-Dihydroxyvitamin D3 [1,25-(OH)2 D3], which by its receptor modulates the expression of CD53 and induces monocytic differentiation of HL-60 leukemic cell (Brackman et al. 1995).
CD53 Protein Level Regulation and Pathology
Activation of neutrophils by stimulation with TNF-α, PDGF, N-formyl-methionyl-leucyl-phenylalanine, or phorbol esters led to a downregulation of the surface expression of CD53 antigen. The downregulatory mechanism implicates a proteolytic digestion triggered by PKC and leads to a complete loss of surface antigen, but the effect is transitory lasting a few hours (Mollinedo et al. 1998). CD53 surface expression was also downregulated in leukocytes from patients with myelodysplastic syndromes (MDSs) and correlates with the activation status of these cells (Kyriakou et al. 2001).
In humans, the only reported phenotype that is associated to CD53 loss was detected in a family with three affected members in which CD53 was not detected in B cells, T cells, or neutrophils. These patients, presented a syndrome characterized by recurrent bacterial and viral infections of heterogeneous origin, which resembles a leukocyte adhesion defect (Mollinedo et al. 1997).
CD53, along with CD81, CD63, TSPAN31 (SAS), and CD82, was expressed at high levels in over 90% of tested Burkitt lymphoma (BL) cell lines. There are no major differences in tetraspanin expression pattern among sporadic or endemic tumors, type of translocation, or Epstein-Barr virus status, suggesting that the cell of origin for these tumors is the same (Ferrer et al. 1998). Neutrophils aging in vitro resulted in a significant increase of CD53 and CD63 expression (Beinert et al. 2000).
In human B-cell malignancies CD53 is expressed at very high levels in tumors that are well differentiated, like multiple myeloma, while its expression is much lower in less-differentiated malignancies, such as diffuse large B-cell lymphomas or follicular lymphomas (Barrena et al. 2005b). The expression of CD53 in combination with CD81 is able to discriminate between two different tumors in a single patient. Combined expression of CD53 and CD81 distinguishes B-chronic lymphocytic leukemia (B-CLL) from splenic marginal zone B-cell lymphoma (SMZL) in the same patient (Barrena et al. 2005a).
CD53 Downregulates Inflammatory Responses
The loss of CD53 protein in mice is able to regulate the production of inflammatory cytokines suggesting CD53 functions as a suppressor of overactivation of inflammatory responses (Lee et al. 2013). A polymorphism in the CD53 promoter is associated to overexpression of CD53 enhancing its role as inhibitor of inflammation (Lee et al. 2013). In myeloid cells CD53 identifies a subset of monocytes with low CD53 and CD81 that is associated with the response to infection. In HIV-1 infection CD53 inversely correlates with viral load, consistent with its role as inhibitor of cytokine production and reduced stimulation of HIV-1-infected cells (Tippett et al. 2013).
In NK cells, CD53 promotes the activation of LFA-1 (β2-integrin lymphocyte function-associated antigen 1) signaling and dampens NK cell effect functions. CD53 facilitates homotypic adhesion of NK cells and promotes cell proliferation by activating the secretion of IL2, instead of the NK effector functions (Lee et al. 2013).
Exosomes, CD53, and Tetraspanin Proteins
CD53 forms part of the tetraspanin web and forms complexes with CD9, CD37, and CD63 among others. These complexes are able to form vesicles, intracellular as endosomes, as well as extracellular that lead to formation of exosomes. Exosomes are extracellular vesicles released by many cell types when multivesicular bodies (MVBs) fuse with the plasma membrane at the end of the endocytic recycling pathway (Andreu and Yanez-Mo 2014). Their participation in exosomes has led to finding that they are a key player in tumor dissemination (Zoller 2009) and contribute to prepare the metastatic tumor cell niche (Costa-Silva et al. 2015; Hoshino et al. 2015). Furthermore, tetraspanins also contribute to different aspects of the tumor phenotype including cell growth, morphology, invasion, tumor engraftment, angiogenesis, and metastasis (Hemler 2014).
The loss of CD53 deficiency is manifested by a clinical syndrome characterized by recurrent infectious diseases by different types of microorganisms, including viruses, fungi, and bacteria, which is somewhat reminiscent of chronic granulomatosis (Mollinedo et al. 1997). This deficiency was detected as a loss of CD53 on the surface of neutrophils and that can be due to either alteration in cell migration or phagocytosis (Mollinedo et al. 1997).
In fish, downregulation of CD53 is associated to increase susceptibility to pathogen invasion and inflammatory reactions (Hou et al. 2016). These results suggest a conserved function for CD53 in evolution.
CD53 is one of the least characterized members of the tetraspanin family. CD53 is integrated in the tetraspanin web, and sends intracellular signals, directly or indirectly via PKC, AKT, and γ-glutamyl transpeptidase (GGT7). Its expression can affect cell survival, resistance to apoptosis, and radiation sensitivity. In B-cell development CD53 is a marker of mature B cells. In human B-cell malignancies, the pattern of tetraspanin expression identifies the developmental stage of the corresponding tumors. The pattern of tetraspanins can be used to differentiate B-cell malignancies in an individual patient with several lymphoid tumors.
- Barrena S, Almeida J, Yunta M, Lopez A, Fernandez-Mosteirin N, Giralt M, et al. Aberrant expression of tetraspanin molecules in B-cell chronic lymphoproliferative disorders and its correlation with normal B-cell maturation. Leukemia. 2005b;19:1376–83. doi: 10.1038/sj.leu.2403822.CrossRefPubMedGoogle Scholar
- Brackman D, Lund-Johansen F, Aarskog D. Expression of leukocyte differentiation antigens during the differentiation of HL-60 cells induced by 1,25-dihydroxyvitamin D3: comparison with the maturation of normal monocytic and granulocytic bone marrow cells. J Leukoc Biol. 1995;58:547–55.PubMedCrossRefGoogle Scholar
- Damjanovich S, Matko J, Matyus L, Szabo Jr G, Szollosi J, Pieri JC, et al. Supramolecular receptor structures in the plasma membrane of lymphocytes revealed by flow cytometric energy transfer, scanning force- and transmission electron-microscopic analyses. Cytometry. 1998;33:225–33.CrossRefPubMedGoogle Scholar
- Lee H, Bae S, Jang J, Choi BW, Park CS, Park JS, et al. CD53, a suppressor of inflammatory cytokine production, is associated with population asthma risk via the functional promoter polymorphism -1560 C>T. Biochim Biophys Acta. 2013;1830:3011–8. doi: 10.1016/j.bbagen.2012.12.030.CrossRefPubMedGoogle Scholar