Basigin Explained

Basigin (BSG) also known as extracellular matrix metalloproteinase inducer (EMMPRIN) or cluster of differentiation 147 (CD147) is a protein that in humans is encoded by the BSG gene.^{[1] [2] [3]} This protein is a determinant for the Ok blood group system. There are three known antigens in the Ok system; the most common being Ok^a (also called OK1), OK2 and OK3. Basigin has been shown to be an essential receptor on red blood cells for the human malaria parasite, Plasmodium falciparum. The common isoform of basigin (basigin-2) has two immunoglobulin domains, and the extended form basigin-1 has three.^[4]

Function

Basigin is a member of the immunoglobulin superfamily, with a structure related to the putative primordial form of the family. As members of the immunoglobulin superfamily play fundamental roles in intercellular recognition involved in various immunologic phenomena, differentiation, and development, basigin is thought also to play a role in intercellular recognition (Miyauchi et al., 1991; Kanekura et al., 1991).^{[5] [6]}

It has a variety of functions. In addition to its metalloproteinase-inducing ability, basigin also regulates several distinct functions, such as spermatogenesis, expression of the monocarboxylate transporter and the responsiveness of lymphocytes.^[2] Basigin is a type I integral membrane receptor that has many ligands, including the cyclophilin (CyP) proteins Cyp-A and CyP-B and certain integrins.^{[7] [8] [9]} Basigin also serves as a receptor for S100A9 and platelet glycoprotein VI, and basigin-1 acts as a receptor for the rod-derived cone viability factor.^[4] It is expressed by many cell types, including epithelial cells, endothelial cells, neural progenitor cells^[10] and leukocytes. The human basigin protein contains 269 amino acids that form two heavily glycosylated C2 type immunoglobulin-like domains at the N-terminal extracellular portion. A second form of basigin has also been characterized that contains one additional immunoglobulin-like domain in its extracellular portion.^[2]

Interactions

Basigin has been shown to interact with Ubiquitin C.^[11]

Basigin has been shown to form a complex with monocarboxylate transporters in the retina of mice. Basigin appears to be required for proper placement of MCTs in the membrane. In the Basigin null mouse, the failure of MCTs to integrate with the membrane may be directly linked to a failure of nutrient transfer in the retinal pigmented epithelium (the lactates transported by MCTs 1, 3, and 4 are essential nutrients for the developing RPE), resulting in loss of sight in the null animal.^[12]

Basigin interacts with the fourth C-type lectin domain in the receptor Endo180^[13] to form a molecular epithelial-mesenchymal transition suppressor complex that if disrupted results in the induction of invasive prostate epithelial cell behavior associated with poor prostate cancer survival.^[14]

Modulators

It have been shown that Atorvastatin suppresses CD147 and MMP-3 expression.^{[15] [16]}

Role in malaria

It has recently (November 2011) been found that basigin is a receptor that is essential to erythrocyte invasion by most strains of Plasmodium falciparum, the most virulent species of the plasmodium parasites that cause human malaria. It is hoped that by developing antibodies to the parasite ligand for Basigin, Rh5, a better vaccine for malaria might be found.^[17] Basigin is bound by the PfRh5 protein on the surface of the malaria parasite.

Role in SARS-CoV-2 infection (COVID-19)

Meplazumab, an anti-CD147 antibody, was tested in patients with SARS-CoV-2 pneumonia.^[18]

Some of these claims have been challenged by another group of scientists who found no evidence of a direct role for basigin in either binding the viral spike protein or promoting lung cell infection.^[19]

More recent studies suggests CD147 as SARS-CoV-2 entry receptor of platelets and megakaryocytes, leading to hyperactivation and thrombosis, that differs from common cold coronavirus CoV-OC43. Incubation of megakaryocyte cells with SARS-CoV-2 resulted in a significant increase in the proinflammatory transcripts LGALS3BP and S100A9. Notably, CD147 antibody-mediated blocking significantly reduced the expression of S100A9, and S100A8 on megakaryocytes following incubation with SARS-CoV-2. These data indicate that megakaryocytes and platelets actively take up SARS-CoV-2 virions, likely via an ACE-2-independent mechanism.^[20]

Another study states that platelets challenged with SARS-CoV-2 undergo activation, dependent on the CD147 receptor.^[21] Yet SARS-CoV-2 does not replicate in human platelets, but initiates cell death.^[22]

Yet another study describes high-interaction coupling of N-RBD of SARS-CoV-2 and CD147 as the main way of infecting lymphocytes allegedly leading to Acquired Immune Deficiency Syndrome.^[23]

Further reading

• Muramatsu T, Miyauchi T . Basigin (CD147): a multifunctional transmembrane protein involved in reproduction, neural function, inflammation and tumor invasion . Histology and Histopathology . 18 . 3 . 981–987 . July 2003 . 12792908 . 10.14670/HH-18.981 . 4635815 .
• Yan L, Zucker S, Toole BP . Roles of the multifunctional glycoprotein, emmprin (basigin; CD147), in tumour progression . Thrombosis and Haemostasis . 93 . 2 . 199–204 . February 2005 . 15711733 . 10.1160/TH04-08-0536 . 27979932 .
• Kasinrerk W, Fiebiger E, Stefanová I, Baumruker T, Knapp W, Stockinger H . Human leukocyte activation antigen M6, a member of the Ig superfamily, is the species homologue of rat OX-47, mouse basigin, and chicken HT7 molecule . Journal of Immunology . 149 . 3 . 847–854 . August 1992 . 10.4049/jimmunol.149.3.847 . 1634773 . 24602674 . free .
• Nabeshima K, Lane WS, Biswas C . Partial sequencing and characterization of the tumor cell-derived collagenase stimulatory factor . Archives of Biochemistry and Biophysics . 285 . 1 . 90–96 . February 1991 . 1846736 . 10.1016/0003-9861(91)90332-D .
• Biswas C, Zhang Y, DeCastro R, Guo H, Nakamura T, Kataoka H, Nabeshima K . The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily . Cancer Research . 55 . 2 . 434–439 . January 1995 . 7812975 .
• Kaname T, Miyauchi T, Kuwano A, Matsuda Y, Muramatsu T, Kajii T . Mapping basigin (BSG), a member of the immunoglobulin superfamily, to 19p13.3 . Cytogenetics and Cell Genetics . 64 . 3–4 . 195–197 . 1993 . 8404035 . 10.1159/000133573 .
• DeCastro R, Zhang Y, Guo H, Kataoka H, Gordon MK, Toole BP, Biswas G . Human keratinocytes express EMMPRIN, an extracellular matrix metalloproteinase inducer . The Journal of Investigative Dermatology . 106 . 6 . 1260–1265 . June 1996 . 8752667 . 10.1111/1523-1747.ep12348959 . free .
• Spring FA, Holmes CH, Simpson KL, Mawby WJ, Mattes MJ, Okubo Y, Parsons SF . The Oka blood group antigen is a marker for the M6 leukocyte activation antigen, the human homolog of OX-47 antigen, basigin and neurothelin, an immunoglobulin superfamily molecule that is widely expressed in human cells and tissues . European Journal of Immunology . 27 . 4 . 891–897 . April 1997 . 9130641 . 10.1002/eji.1830270414 . 23072979 .
• Berditchevski F, Chang S, Bodorova J, Hemler ME . Generation of monoclonal antibodies to integrin-associated proteins. Evidence that alpha3beta1 complexes with EMMPRIN/basigin/OX47/M6 . The Journal of Biological Chemistry . 272 . 46 . 29174–29180 . November 1997 . 9360995 . 10.1074/jbc.272.46.29174 . free .
• Guo H, Majmudar G, Jensen TC, Biswas C, Toole BP, Gordon MK . Characterization of the gene for human EMMPRIN, a tumor cell surface inducer of matrix metalloproteinases . Gene . 220 . 1–2 . 99–108 . October 1998 . 9767135 . 10.1016/S0378-1119(98)00400-4 .
• Guo H, Li R, Zucker S, Toole BP . EMMPRIN (CD147), an inducer of matrix metalloproteinase synthesis, also binds interstitial collagenase to the tumor cell surface . Cancer Research . 60 . 4 . 888–891 . February 2000 . 10706100 .
• Kirk P, Wilson MC, Heddle C, Brown MH, Barclay AN, Halestrap AP . CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression . The EMBO Journal . 19 . 15 . 3896–3904 . August 2000 . 10921872 . 306613 . 10.1093/emboj/19.15.3896 .
• Yurchenko V, O'Connor M, Dai WW, Guo H, Toole B, Sherry B, Bukrinsky M . CD147 is a signaling receptor for cyclophilin B . Biochemical and Biophysical Research Communications . 288 . 4 . 786–788 . November 2001 . 11688976 . 10.1006/bbrc.2001.5847 .
• Yurchenko V, Zybarth G, O'Connor M, Dai WW, Franchin G, Hao T, Guo H, Hung HC, Toole B, Gallay P, Sherry B, Bukrinsky M . Active site residues of cyclophilin A are crucial for its signaling activity via CD147 . The Journal of Biological Chemistry . 277 . 25 . 22959–22965 . June 2002 . 11943775 . 10.1074/jbc.M201593200 . free .
• Major TC, Liang L, Lu X, Rosebury W, Bocan TM . Extracellular matrix metalloproteinase inducer (EMMPRIN) is induced upon monocyte differentiation and is expressed in human atheroma . Arteriosclerosis, Thrombosis, and Vascular Biology . 22 . 7 . 1200–1207 . July 2002 . 12117738 . 10.1161/01.ATV.0000021411.53577.1C . free .
• Taylor PM, Woodfield RJ, Hodgkin MN, Pettitt TR, Martin A, Kerr DJ, Wakelam MJ . Breast cancer cell-derived EMMPRIN stimulates fibroblast MMP2 release through a phospholipase A(2) and 5-lipoxygenase catalyzed pathway . Oncogene . 21 . 37 . 5765–5772 . August 2002 . 12173047 . 10.1038/sj.onc.1205702 . free .
• Thorns C, Feller AC, Merz H . EMMPRIN (CD 147) is expressed in Hodgkin's lymphoma and anaplastic large cell lymphoma. An immunohistochemical study of 60 cases . Anticancer Research . 22 . 4 . 1983–1986 . 2002 . 12174874 . .

External links

• • Ok blood group system at BGMUT Blood Group Antigen Gene Mutation Database at NCBI, NIH
• PDBe-KB provides an overview of all the structure information available in the PDB for Human Basigin

Notes and References

1. Kasinrerk W, Fiebiger E, Stefanová I, Baumruker T, Knapp W, Stockinger H . Human leukocyte activation antigen M6, a member of the Ig superfamily, is the species homologue of rat OX-47, mouse basigin, and chicken HT7 molecule . Journal of Immunology . 149 . 3 . 847–854 . August 1992 . 10.4049/jimmunol.149.3.847 . 1634773 . 24602674 . free .
2. Yurchenko V, Constant S, Bukrinsky M . Dealing with the family: CD147 interactions with cyclophilins . Immunology . 117 . 3 . 301–309 . March 2006 . 16476049 . 1782239 . 10.1111/j.1365-2567.2005.02316.x .
3. Miyauchi T, Masuzawa Y, Muramatsu T . The basigin group of the immunoglobulin superfamily: complete conservation of a segment in and around transmembrane domains of human and mouse basigin and chicken HT7 antigen . Journal of Biochemistry . 110 . 5 . 770–774 . November 1991 . 1783610 . 10.1093/oxfordjournals.jbchem.a123657 .
4. Muramatsu T . Basigin (CD147), a multifunctional transmembrane glycoprotein with various binding partners . Journal of Biochemistry . 159 . 5 . 481–490 . May 2016 . 26684586 . 4846773 . 10.1093/jb/mvv127 .
5. Web site: Entrez Gene: BSG basigin (Ok blood group).
6. Kanekura T, Chen X, Kanzaki T . Basigin (CD147) is expressed on melanoma cells and induces tumor cell invasion by stimulating production of matrix metalloproteinases by fibroblasts . International Journal of Cancer . 99 . 4 . 520–528 . June 2002 . 11992541 . 10.1002/ijc.10390 . 37384660 . free .
7. Yurchenko V, Zybarth G, O'Connor M, Dai WW, Franchin G, Hao T, Guo H, Hung HC, Toole B, Gallay P, Sherry B, Bukrinsky M . Active site residues of cyclophilin A are crucial for its signaling activity via CD147 . The Journal of Biological Chemistry . 277 . 25 . 22959–22965 . June 2002 . 11943775 . 10.1074/jbc.M201593200 . free .
8. Yurchenko V, O'Connor M, Dai WW, Guo H, Toole B, Sherry B, Bukrinsky M . CD147 is a signaling receptor for cyclophilin B . Biochemical and Biophysical Research Communications . 288 . 4 . 786–788 . November 2001 . 11688976 . 10.1006/bbrc.2001.5847 .
9. Berditchevski F, Chang S, Bodorova J, Hemler ME . Generation of monoclonal antibodies to integrin-associated proteins. Evidence that alpha3beta1 complexes with EMMPRIN/basigin/OX47/M6 . The Journal of Biological Chemistry . 272 . 46 . 29174–29180 . November 1997 . 9360995 . 10.1074/jbc.272.46.29174 . free .
10. Kanemitsu M, Tsupykov O, Potter G, Boitard M, Salmon P, Zgraggen E, Gascon E, Skibo G, Dayer AG, Kiss JZ . EMMPRIN overexpression in SVZ neural progenitor cells increases their migration towards ischemic cortex . Experimental Neurology . 297 . 14–24 . November 2017 . 28716558 . 10.1016/j.expneurol.2017.07.009 . 4587600 .
11. Wang WJ, Li QQ, Xu JD, Cao XX, Li HX, Tang F, Chen Q, Yang JM, Xu ZD, Liu XP . Interaction between CD147 and P-glycoprotein and their regulation by ubiquitination in breast cancer cells . Chemotherapy . 54 . 4 . 291–301 . 2008 . 18689982 . 10.1159/000151225 . 7260048 .
12. Philp NJ, Ochrietor JD, Rudoy C, Muramatsu T, Linser PJ . Loss of MCT1, MCT3, and MCT4 expression in the retinal pigment epithelium and neural retina of the 5A11/basigin-null mouse . Investigative Ophthalmology & Visual Science . 44 . 3 . 1305–1311 . March 2003 . 12601063 . 10.1167/iovs.02-0552 . free .
13. Web site: WikiGenes: MRC2 - mannose receptor C, type 2 Homo sapiens .
14. Rodriguez-Teja M, Gronau JH, Minamidate A, Darby S, Gaughan L, Robson C, Mauri F, Waxman J, Sturge J . Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147 . Molecular Cancer Research . 13 . 3 . 538–547 . March 2015 . 25381222 . 10.1158/1541-7786.MCR-14-0344-T . 9946106 . free .
15. Yi F, Jiang L, Xu H, Dai F, Zhou L . Atorvastatin suppresses CD147 and MMP-3 expression and improves histological and neurological outcomes in an animal model of intracerebral hemorrhage . International Journal of Clinical and Experimental Medicine . 11 . 9 . 9301–9311 .
16. Sasidhar MV, Chevooru SK, Eickelberg O, Hartung HP, Neuhaus O . Downregulation of monocytic differentiation via modulation of CD147 by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors . PloS One . 12 . 12 . e0189701 . 18 December 2017 . 29253870 . 5734787 . 10.1371/journal.pone.0189701 . free . 2017PLoSO..1289701S .
17. Crosnier C, Bustamante LY, Bartholdson SJ, Bei AK, Theron M, Uchikawa M, Mboup S, Ndir O, Kwiatkowski DP, Duraisingh MT, Rayner JC, Wright GJ . Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum . Nature . 480 . 7378 . 534–537 . November 2011 . 22080952 . 3245779 . 10.1038/nature10606 . 2011Natur.480..534C .
18. Bian H, Zheng ZH, Wei D, Zhang Z, Kang WZ, Hao CQ, Dong K, Kang W, Xia JL, Miao JL, Xie RH . 2020 . Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial . bioRxiv . 10.1101/2020.03.21.20040691 . free .
19. Shilts J, Crozier TW, Greenwood EJ, Lehner PJ, Wright GJ . No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor . Scientific Reports . 11 . 1 . 413 . January 2021 . 33432067 . 7801465 . 10.1038/s41598-020-80464-1 . free .
20. Barrett TJ, Bilaloglu S, Cornwell M, Burgess HM, Virginio VW, Drenkova K, Ibrahim H, Yuriditsky E, Aphinyanaphongs Y, Lifshitz M, Xia Liang F, Alejo J, Smith G, Pittaluga S, Rapkiewicz AV, Wang J, Iancu-Rubin C, Mohr I, Ruggles K, Stapleford KA, Hochman J, Berger JS . Platelets contribute to disease severity in COVID-19 . Journal of Thrombosis and Haemostasis . 19 . 12 . 3139–3153 . December 2021 . 34538015 . 8646651 . 10.1111/jth.15534 .
21. Maugeri N, De Lorenzo R, Clementi N, Antonia Diotti R, Criscuolo E, Godino C, Tresoldi C, Angels For Covid-BioB Study Group B, Bonini C, Clementi M, Mancini N, Ciceri F, Rovere-Querini P, Manfredi AA . Unconventional CD147-dependent platelet activation elicited by SARS-CoV-2 in COVID-19 . Journal of Thrombosis and Haemostasis . 434–448 . October 2021 . 20 . 2 . 34710269 . 8646617 . 10.1111/jth.15575 .
22. Koupenova-Zamor M, Corkrey HA, Vitseva O, Tanriverdi K, Somasundaran M, Liu P, Soofi S, Parsi KM, Cousineau A, Maehr R, Wang JP . SARS-CoV-2 Initiates Programmed Cell Death in Platelets . September 2021 . Circulation Research . 129 . 6 . 631-646 . 10.1161/CIRCRESAHA.121.319117 . 8409903 .
23. Ximeno-Rodríguez I, Blanco-delRío I, Astigarraga E, Barreda-Gómez G . Acquired Immune Deficiency Syndrome correlation with SARS-CoV-2 N genotypes . Biomedical Journal . 47 . 3 . 100650 . June 2024 . 37604249 . 10.1016/j.bj.2023.100650 . 261042891 . free .