Cell Surface Expression of CD147/EMMPRIN Is Regulated by Cyclophilin 60

CD147, also known as extracellular matrix metalloproteinase inducer, is a regulator of matrix metalloproteinase production and also serves as a signaling receptor for extracellular cyclophilins. Previously, we demonstrated that cell surface expression of CD147 is sensitive to cyclophilin-binding drug cyclosporin A, suggesting involvement of a cyclophilin in the regulation of intracellular transport of CD147. In this report, we identify this cyclophilin as cyclophilin 60 (Cyp60), a distinct member of the cyclophilin family of proteins. CD147 co-immunoprecipitated with Cyp60, and confocal immunofluorescent microscopy revealed intracellular co-localization of Cyp60 and CD147. This interaction with Cyp60 involved proline 211 of CD147, which was shown previously to be critical for interaction between CD147 and another cyclophilin, cyclophilin A, in solution. Mutation of this proline residue abrogated co-immunoprecipitation of CD147 and Cyp60 and reduced surface expression of CD147 on the plasma membrane. Suppression of Cyp60 expression using RNA interference had an effect similar to that of cyclosporin A: reduction of cell surface expression of CD147. These results suggest that Cyp60 plays an important role in the translocation of CD147 to the cell surface. Therefore, Cyp60 may present a novel target for therapeutic interventions in diseases where CD147 functions as a pathogenic factor, such as cancer, human immunodeficiency virus infection, or rheumatoid arthritis. CD147, also known as extracellular matrix metalloproteinase inducer, is a regulator of matrix metalloproteinase production and also serves as a signaling receptor for extracellular cyclophilins. Previously, we demonstrated that cell surface expression of CD147 is sensitive to cyclophilin-binding drug cyclosporin A, suggesting involvement of a cyclophilin in the regulation of intracellular transport of CD147. In this report, we identify this cyclophilin as cyclophilin 60 (Cyp60), a distinct member of the cyclophilin family of proteins. CD147 co-immunoprecipitated with Cyp60, and confocal immunofluorescent microscopy revealed intracellular co-localization of Cyp60 and CD147. This interaction with Cyp60 involved proline 211 of CD147, which was shown previously to be critical for interaction between CD147 and another cyclophilin, cyclophilin A, in solution. Mutation of this proline residue abrogated co-immunoprecipitation of CD147 and Cyp60 and reduced surface expression of CD147 on the plasma membrane. Suppression of Cyp60 expression using RNA interference had an effect similar to that of cyclosporin A: reduction of cell surface expression of CD147. These results suggest that Cyp60 plays an important role in the translocation of CD147 to the cell surface. Therefore, Cyp60 may present a novel target for therapeutic interventions in diseases where CD147 functions as a pathogenic factor, such as cancer, human immunodeficiency virus infection, or rheumatoid arthritis. Cyclophilins are a family of proteins which share peptidyl-prolyl cis-trans isomerase (PPIase) 1The abbreviations used are: PPIase, peptidyl-prolyl cis-trans-isomerase; CypA, cyclophilin A; Cyp60, cyclophilin 60; EMMPRIN, extracellular matrix metalloproteinase inducer; GFP, green fluorescent protein; CHO, Chinese hamster ovary; HEK, human embryonic kidney; CsA, cyclosporin A; PE, phycoerythrin; PBS, phosphate-buffered saline; siRNA, small interfering RNA; FAM, carboxyfluorescein; MFI, mean fluorescent intensity. activity and serve as receptors for the immunosuppressive drug cyclosporin A (CsA). The PPIase activity of cyclophilins is the basis for their proposed role in protein folding (1Ivery M.T. Med. Res. Rev. 2000; 20: 452-484Crossref PubMed Scopus (116) Google Scholar). Another established activity of cyclophilins is regulation of protein trafficking in cells. Cyclophilin A has been shown to be a component of the transport complexes that regulate surface expression of asialoglycoprotein receptor expression in human cells (2Huang T. Deng H. Wolkoff A.W. Stockert R.J. J. Biol. Chem. 2002; 277: 37798-37803Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). The Drosophila cyclophilin homolog, NinaA, participates in trafficking of rhodopsin, the most abundant subclass of photoreceptors (3Colley N.J. Baker E.K. Stamnes M.A. Zuker C.S. Cell. 1991; 67: 255-263Abstract Full Text PDF PubMed Scopus (278) Google Scholar, 4Baker E.K. Colley N.J. Zuker C.S. EMBO J. 1994; 13: 4886-4895Crossref PubMed Scopus (276) Google Scholar, 5Ferreira P.A. Nakayama T.A. Pak W.L. Travis G.H. Nature. 1996; 383: 637-640Crossref PubMed Scopus (189) Google Scholar). NinaA and its mammalian counterparts are retina-expressed integral membrane proteins with the cyclophilin-homologous domain located in the lumen of the endoplasmic reticulum and intracellular transport vehicles (4Baker E.K. Colley N.J. Zuker C.S. EMBO J. 1994; 13: 4886-4895Crossref PubMed Scopus (276) Google Scholar, 6Ferreira P.A. Hom J.T. Pak W.L. J. Biol. Chem. 1995; 270: 23179-23188Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 7Stamnes M.A. Shieh B.H. Chuman L. Harris G.L. Zuker C.S. Cell. 1991; 65: 219-227Abstract Full Text PDF PubMed Scopus (221) Google Scholar). In all these examples cyclophilins were found to form a specific stable complex with the substrate, suggesting that they function as a chaperone escorting its protein substrate through the traffic pathway. Recent reports suggest that cyclophilins may be involved in cell surface externalization of three other proteins, namely, insulin receptor (8Shiraishi S. Yokoo H. Kobayashi H. Yanagita T. Uezono Y. Minami S. Takasaki M. Wada A. Neurosci. Lett. 2000; 293: 211-215Crossref PubMed Scopus (27) Google Scholar), Flt3 ligand (13Chklovskaia E. Nissen C. Landmann L. Rahner C. Pfister O. Wodnar-Filipowicz A. Blood. 2001; 97: 1027-1034Crossref PubMed Scopus (44) Google Scholar), and CD147 (25Yurchenko V. Pushkarsky T. Li J.H. Dai W.W. Sherry B. Bukrinsky M. J. Biol. Chem. 2005; 280: 17013-17019Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). In all these cases, treatment of the cells with CsA reduced the cell surface expression of these proteins (insulin receptor, Flt3L, CD147) without altering their total cellular levels, suggesting a block at the level of transition from the endoplasmic reticulum to the plasma membrane. The cyclophilin(s) involved in regulation of trafficking of these proteins have not yet been identified. The mechanisms by which cyclophilins regulate protein trafficking remain unknown. Molecular studies of Drosophila ninaA mutants have shown that CsA has only a minor effect on rhodopsin transport, and ninaA mutations need not be within the PPIase/CsA-binding domain to cause severe reductions in rhodopsin levels (10Ondek B. Hardy R.W. Baker E.K. Stamnes M.A. Shieh B.H. Zuker C.S. J. Biol. Chem. 1992; 267: 16460-16466Abstract Full Text PDF PubMed Google Scholar, 11Schneuwly S. Shortridge R.D. Larrivee D.C. Ono T. Ozaki M. Pak W.L. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 5390-5394Crossref PubMed Scopus (151) Google Scholar, 12Shieh B.H. Stamnes M.A. Seavello S. Harris G.L. Zuker C.S. Nature. 1989; 338: 67-70Crossref PubMed Scopus (215) Google Scholar). On the other hand, cell surface expression of the Flt3 ligand, insulin receptor, and CD147 was greatly reduced by CsA, suggesting involvement of the PPIase/CsA-binding domain of cyclophilin in the regulation of trafficking of these proteins (8Shiraishi S. Yokoo H. Kobayashi H. Yanagita T. Uezono Y. Minami S. Takasaki M. Wada A. Neurosci. Lett. 2000; 293: 211-215Crossref PubMed Scopus (27) Google Scholar, 13Chklovskaia E. Nissen C. Landmann L. Rahner C. Pfister O. Wodnar-Filipowicz A. Blood. 2001; 97: 1027-1034Crossref PubMed Scopus (44) Google Scholar, 25Yurchenko V. Pushkarsky T. Li J.H. Dai W.W. Sherry B. Bukrinsky M. J. Biol. Chem. 2005; 280: 17013-17019Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). The cyclophilin-interacting site has been identified in CD147 as the proline-containing region at the end of the transmembrane helix adjacent to the extracellular domain (25Yurchenko V. Pushkarsky T. Li J.H. Dai W.W. Sherry B. Bukrinsky M. J. Biol. Chem. 2005; 280: 17013-17019Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). CD147 is a type 1 integral membrane protein shown to regulate intercellular adhesion pathways through an intracellular signaling-mediated mechanism (14Kasinrerk W. Tokrasinwit N. Phunpae P. Immunology. 1999; 96: 184-192Crossref PubMed Scopus (72) Google Scholar). It is also known as extracellular matrix metalloproteinase inducer (EMMPRIN) and EMMPRIN expressed by cultured tumor cells stimulates fibroblasts to produce very high levels of collagenase activity, which likely facilitates tumor metastasis (15Ellis S.M. Nabeshima K. Biswas C. Cancer Res. 1989; 49: 3385-3391PubMed Google Scholar, 16Biswas C. Zhang Y. DeCastro R. Guo H. Nakamura T. Kataoka H. Nabeshima K. Cancer Res. 1995; 55: 434-439PubMed Google Scholar). Supporting its key role in the processes of tumorigenesis and metastasis, EMMPRIN was reported as one of the most constantly up-regulated mRNA in metastatic cells (17Klein C.A. Seidl S. Petat-Dutter K. Offner S. Geigl J.B. Schmidt-Kittler O. Wendler N. Passlick B. Huber R.M. Schlimok G. Baeuerle P.A. Riethmuller G. Nat. Biotechnol. 2002; 20: 387-392Crossref PubMed Scopus (248) Google Scholar). Another physiologic role of CD147 relates to its activity as a receptor for extracellular cyclophilins (18Yurchenko V. Zybarth G. O'Connor M. Dai W.W. Franchin G. Hao T. Guo H. Hung H.C. Toole B. Gallay P. Sherry B. Bukrinsky M. J. Biol. Chem. 2002; 277: 22959-22965Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 19Yurchenko V. O'Connor M. Dai W.W. Guo H. Toole B. Sherry B. Bukrinsky M. Biochem. Biophys. Res. Commun. 2001; 288: 786-788Crossref PubMed Scopus (121) Google Scholar). Since cyclophilins emerge as mediators of intercellular communication that may regulate chemotactic responses in many physiologic and pathologic processes, such as cell-mediated immunity and inflammation (20Bukrinsky M.I. Trends Immunol. 2002; 23: 323-325Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar), regulation of CD147 expression may determine the outcome of these events. A related activity of CD147 is its role as a cofactor in human immunodeficiency virus type 1 infection, where CD147 likely functions as a receptor for virion-associated CypA, thus increasing virus entry into target cell (21Pushkarsky T. Zybarth G. Dubrovsky L. Yurchenko V. Tang H. Guo H. Toole B. Sherry B. Bukrinsky M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 6360-6365Crossref PubMed Scopus (210) Google Scholar). In this report, we identify the cyclophilin regulating cell surface expression of CD147 as cyclophilin 60 (Cyp60), a previously described 60-kDa member of the cyclophilin family of proteins (22Wang B.B. Hayenga K.J. Payan D.G. Fisher J.M. Biochem. J. 1996; 314: 313-319Crossref PubMed Scopus (33) Google Scholar). These results suggest that Cyp60 may be an important regulator of intracellular transport. Antibodies and Reagents—Fluorescein isothiocyanate- or PE-conjugated anti-CD147 monoclonal antibodies were purchased from Ancell (Bayport, MN), peridinin-chlorophyll protein-cojugated anti-CD4 monoclonal antibody was from BD Biosciences, and PE-labeled anti-CD71 monoclonal antibody was from CALTAG Laboratories (Burlingame, CA). Anti-GM130 mouse monoclonal antibody was from BD Biosciences, mouse monoclonal anti-FLAG antibody was from Chemicon (Temecula, CA), rabbit polyclonal anti-CypA antibody was from United States Biological (Swampscott, MA), and rhodamine and Cy5-labeled goat anti-mouse and anti-rabbit IgG were from Jackson ImmunoResearch Laboratories (West Grove, PA). Cyclosporin A was purchased from Sigma, TOPRO-3 iodide was from Molecular Probes (Eugene, OR). Co-immunoprecipitation—CHO cells were transfected with GFP- or CD147.wt-GFP-expressing vectors, cultured for 15 h, and harvested with 2 mm EDTA. Approximately 6 × 105 cells were lysed in TNEP lysis buffer (25 mm Tris-HCl, pH 7.4, 150 mm NaCl, 5 mm EDTA, 1 mm phenylmethylsulfonyl fluoride, 1 μg/ml aprotinin, 1 μg/ml leupeptin, 1% Triton X-100), spun at 14,000 rpm at 4 °C for 20 min in an Eppendorf microcentrifuge, and the supernatant (300 μl) was collected and incubated on ice for 1 h with mouse monoclonal anti-GFP antibody (Roche Diagnostics Corp., Mannheim, Germany). Immune complexes were precipitated by adding protein G beads (50 μl of 50% slurry in PBS) for 1 h at room temperature. Proteins were eluted from beads by adding non-reducing sample buffer to each sample and heating at 60 °C for 3 min. Supernatants were loaded on 12% SDS-PAGE gel. Western blotting was performed using rabbit polyclonal anti-CypA (1:1000; Affinity Bioreagents) or anti-GFP (1:5000; Abcam, Cambridge, MA) antibodies and developed by the ECL procedure (Amersham Biosciences, Uppsala, Sweden). HEK 293T cells were co-transfected with vector S. M. M. N. Nakayama J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google with or were for 15 h and harvested with 2 mm EDTA. Approximately 6 × 105 cells were lysed in TNEP lysis buffer (25 mm Tris-HCl, pH 7.4, 150 mm NaCl, 5 mm EDTA, 1 mm phenylmethylsulfonyl fluoride, 1 μg/ml aprotinin, 1 μg/ml leupeptin, 1% Triton X-100), and cell were spun at 14,000 rpm at 4 °C for 20 min in an Eppendorf and incubated with mouse IgG for 1 h at 4 by a at room with protein beads to was to and mouse monoclonal anti-FLAG antibody or mouse monoclonal anti-GFP antibody (Roche Diagnostics was to the an at 4 protein beads were and complexes on and by Western blotting using rabbit polyclonal anti-FLAG goat polyclonal anti-CD147 CA), or rabbit polyclonal anti-GFP antibody on were for 20 min at room with in cells transfected or not with were incubated for 1 h at room with a rabbit polyclonal antibody Cyp60 or polyclonal anti-FLAG antibody in and were incubated for 1 h at room with goat polyclonal antibodies to rabbit at a of and with were with a of and and with a with a cells transfected with were by in mm in for 15 min at room and incubated for 2 h at room using mouse monoclonal antibody in goat in PBS, by with goat anti-mouse IgG ImmunoResearch at HEK 293T cells co-transfected with and were using mouse monoclonal anti-FLAG antibody and goat anti-mouse IgG ImmunoResearch was with the antibody to the of and HEK 293T cells were using a with an using of CD147 293T embryonic cells × were with of for min at were and incubated in with or without CsA were collected for the the and were with PE-conjugated anti-CD147 or anti-CD71 antibodies or and by Suppression of Cyp60 by RNA with at the end were by The of the of was as The small three in the were transfected into HEK 293T cells using Cyclophilin 60 with results that cell surface expression of CD147 is by a cyclophilin (25Yurchenko V. Pushkarsky T. Li J.H. Dai W.W. Sherry B. Bukrinsky M. J. Biol. Chem. 2005; 280: 17013-17019Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). also that of proline 211 in the transmembrane domain of CD147 of to CD147 in and of CD147 surface expression to demonstrated that CD147 has on the cell surface not suggesting that its is a Since CD147 interaction with cyclophilin of CD147 to the plasma membrane (25Yurchenko V. Pushkarsky T. Li J.H. Dai W.W. Sherry B. Bukrinsky M. J. Biol. Chem. 2005; 280: 17013-17019Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar), we that the to are in cells by high level expression of CD147. CD147 with cyclophilin, we performed a co-immunoprecipitation studies (25Yurchenko V. Pushkarsky T. Li J.H. Dai W.W. Sherry B. Bukrinsky M. J. Biol. Chem. 2005; 280: 17013-17019Abstract Full Text Full Text PDF PubMed Scopus (63) Google were in we used the cells in the cells were transfected with the or and in the or of CsA for cells or cells transfected with the vector were used as complexes were with anti-GFP antibody and by Western blotting using antibodies to most abundant cellular or It be that the polyclonal anti-CypA antibody used most cyclophilins in not Therefore, was to with hamster CypA, with CD147. was revealed in the from cells transfected with the antibody to revealed a with a on the of to a protein with an of 60 The of this was in the from cells with demonstrated of CD147 cell surface expression to CsA in and such was in the from cells transfected with the in to in or in or cells that the of proteins was loaded in each we the and using anti-GFP and and a the revealed in cells transfected with or to of the protein that CD147 with a cyclophilin that has a of cyclophilins described in the only one Cyp60, has been reported to have a to 60 (22Wang B.B. Hayenga K.J. Payan D.G. Fisher J.M. Biochem. J. 1996; 314: 313-319Crossref PubMed Scopus (33) Google Scholar). determine Cyp60 with CD147 in human we transfected HEK 293T cells with Cyp60, using anti-FLAG and for CD147 in the using anti-CD147 CD147 was found in the used to the of was not precipitated not on the to of the In a was revealed in the with the anti-GFP antibody from HEK 293T cells co-transfected with and Cyclosporin A greatly reduced the of with the that interaction the site of between CD147 and Cyp60 was also abrogated by the of the proline residue 211 which was shown previously to be critical for interaction between CD147 and cyclophilin A in (25Yurchenko V. Pushkarsky T. Li J.H. Dai W.W. Sherry B. Bukrinsky M. J. Biol. Chem. 2005; 280: 17013-17019Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). these results that Cyp60 with CD147 in a this interaction also the residue of CD147. Cyp60 the of Previously, we demonstrated that cell surface expression of CD147 is sensitive to CsA (25Yurchenko V. Pushkarsky T. Li J.H. Dai W.W. Sherry B. Bukrinsky M. J. Biol. Chem. 2005; 280: 17013-17019Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). interaction for the to CsA, we Cyp60 expression in HEK 293T cells using the RNA interference greatly reduced expression of Cyp60 without expression of This effect of was by three in the Cyp60 thus the of the the effect of Cyp60 on of cell surface CD147 treatment with which is used as a plasma membrane protein D.G. J. 1996; PubMed Google Scholar, 25Yurchenko V. Pushkarsky T. Li J.H. Dai W.W. Sherry B. Bukrinsky M. J. Biol. Chem. 2005; 280: 17013-17019Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). shown in CD147 surface expression on HEK 293T cells was greatly reduced not by treatment with was h of in was to the in with CsA which is In the of CsA, of CD147 on the cell surface was at the h expression of CD147 as mean fluorescent was in cells in cells with mean such reduction was with another transmembrane receptor thus the of the CsA CD147 in HEK 293T cells transfected with or The used for this were with FAM, thus to on transfected cells. in that surface expression of CD147 was reduced in transfected with as with transfected with The reduction was similar to that with CsA and the in the suggesting that Cyp60 is the likely the cyclophilin that CD147 intracellular This was by that treatment with CsA not CD147 surface expression in cells transfected with in The were specific for CD147, as expression of the receptor was not by in the in with its to CsA in and in the in in was by a of CsA and in the in Cyp60 with was previously reported to to the cell in transfected cells (22Wang B.B. Hayenga K.J. Payan D.G. Fisher J.M. Biochem. J. 1996; 314: 313-319Crossref PubMed Scopus (33) Google Scholar). anti-FLAG we the intracellular of in transfected cells. shown in in many cells was found to be between the and In HEK 293T cells co-transfected with and co-localization of Cyp60 and CD147 was the most co-localization of these proteins at the plasma membrane by in the on Therefore, Cyp60 to CD147 to the plasma thus as a chaperone these results the where cyclophilin interaction with the proline-containing region adjacent to the transmembrane domain of CD147, CD147 transport from the to the plasma membrane. The in this that the surface expression of CD147 is by a distinct member of the cyclophilin The mechanism of this activity interaction of Cyp60 with the proline-containing region within or adjacent to the transmembrane domain CD147. this interaction was by CsA or by the critical proline expression of CD147 on the cell surface was This effect is with the proposed role of cyclophilins in the transport of the proteins from the endoplasmic reticulum to the plasma membrane (4Baker E.K. Colley N.J. Zuker C.S. EMBO J. 1994; 13: 4886-4895Crossref PubMed Scopus (276) Google Scholar, S. Yokoo H. Kobayashi H. Yanagita T. Uezono Y. Minami S. Takasaki M. Wada A. Neurosci. Lett. 2000; 293: 211-215Crossref PubMed Scopus (27) Google Scholar). Cyp60 has been previously from a in a using as (22Wang B.B. Hayenga K.J. Payan D.G. Fisher J.M. Biochem. J. 1996; 314: 313-319Crossref PubMed Scopus (33) Google Scholar). and reported of Cyp60 and that may chaperone proteins or be involved in their folding (22Wang B.B. Hayenga K.J. Payan D.G. Fisher J.M. Biochem. J. 1996; 314: 313-319Crossref PubMed Scopus (33) Google Scholar). demonstrated that in cells Cyp60 to the and the of Cyp60 of a specific antibody that this cyclophilin from the other of this family of proteins. Cyp60 with CD147 at the plasma membrane suggesting that this cyclophilin may function as a chaperone escorting CD147 through the pathway. Previously, a similar function was described for Drosophila cyclophilin NinaA, which of its protein target rhodopsin (4Baker E.K. Colley N.J. Zuker C.S. EMBO J. 1994; 13: 4886-4895Crossref PubMed Scopus (276) Google Scholar). Cyp60, is the mammalian cyclophilin in protein transport to the plasma membrane. It to be the only cyclophilin involved in CD147 membrane transport, as cyclosporin A treatment not to the effect of Cyp60 interaction with CD147 proline 211 in the transmembrane This proline residue is to the extracellular domain of CD147 and is likely to be in the lumen of the (25Yurchenko V. Pushkarsky T. Li J.H. Dai W.W. Sherry B. Bukrinsky M. J. Biol. Chem. 2005; 280: 17013-17019Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). Therefore, the domain of Cyp60 be on the of the membrane to this NinaA, Cyp60 is not to be an integral transmembrane is likely into the In is a protein and thus may not have to of CD147, which may was co-immunoprecipitated with CD147, to CD147 in (25Yurchenko V. Pushkarsky T. Li J.H. Dai W.W. Sherry B. Bukrinsky M. J. Biol. Chem. 2005; 280: 17013-17019Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). CD147 has been shown to with other proteins that may its of CD147 with was by a critical residue in the transmembrane domain of CD147, CD147 the plasma membrane J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). CD147 also with on a cell surface and this interaction to regulate and activity of CD147 W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), its role in CD147 cell surface expression has not been in the domain of CD147 was identified as a which CD147 to the membrane in G. J. E. Biol. Cell. PubMed Scopus Google Scholar). This to function only in cell was not in human cells G. J. E. Biol. Cell. PubMed Scopus Google suggesting that interaction with regulator of protein studies these to suggest a of CD147 that CD147 expression is by Cyp60 for diseases where CD147 functions as a pathogenic is rheumatoid where levels of CD147 on and cyclophilin in have been shown to with Li J. M. T. S. 2000; PubMed Scopus Google Scholar). Another is where CD147 (EMMPRIN) was shown to be on the surface of tumor cells and may a key role in matrix metalloproteinase production and tumor cell T. Nabeshima K. Toole K. Y. T. M. S. J. 2000; PubMed Scopus Google Scholar, J. Cancer Res. 2001; Google Scholar). another is human immunodeficiency virus infection, which on CD147 for high virus (21Pushkarsky T. Zybarth G. Dubrovsky L. Yurchenko V. Tang H. Guo H. Toole B. Sherry B. Bukrinsky M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 6360-6365Crossref PubMed Scopus (210) Google Scholar). results that expression of CD147 be reduced by Cyp60, such as CsA or siRNA, suggesting to treatment of rheumatoid or of In results identify a novel mechanism for regulation of plasma membrane expression of by a family of related integral membrane proteins. This mechanism interaction between the proline-containing transmembrane region of CD147 and cyclophilin which to trafficking of the protein from the to the plasma membrane. studies identify other proteins by Cyp60 and determine the involved in this and the for with confocal of the Bukrinsky for are to for the of this