Ligand Binding Determines Whether CD46 Is Internalized by Clathrin-coated Pits or Macropinocytosis (2003)

CD46 is a ubiquitous human cell surface receptor for the complement components C3b and C4b and for various pathogens, including the measles virus and human herpes virus 6. Ligand binding to CD46 affects (i) protection of autologous cells from complement attack by breakdown of complement components, (ii) intracellular signals that affect the regulation of immune cell function, (iii) antigen presentation, and (iv) down-regulation of cell surface CD46. Recent evidence indicates that CD46 signaling can link innate and acquired immune function. The molecular mechanisms for these processes and the importance of intracellular trafficking of the receptor have not yet been elucidated. We demonstrate here that, in nonlymphoid cells, CD46 is constitutively internalized via clathrin-coated pits, traffics to multivesicular bodies, and is recycled to the cell surface. However, cross-linking of CD46 at the cell surface, by either multivalent antibody or by measles virus, induces pseudopodia that engulf the ligand in a process similar to macropinocytosis, and leads to the degradation of cell surface CD46. Thus, we have elucidated two pathways for CD46 internalization, which are regulated by the valence of cross-linking of CD46 and which utilize either clathrin-coated pits or pseudopodial extension. This has important implications for CD46 signaling, antigen presentation, CD46 down-regulation, and engulfment of pathogens. CD46 is a ubiquitous human cell surface receptor for the complement components C3b and C4b and for various pathogens, including the measles virus and human herpes virus 6. Ligand binding to CD46 affects (i) protection of autologous cells from complement attack by breakdown of complement components, (ii) intracellular signals that affect the regulation of immune cell function, (iii) antigen presentation, and (iv) down-regulation of cell surface CD46. Recent evidence indicates that CD46 signaling can link innate and acquired immune function. The molecular mechanisms for these processes and the importance of intracellular trafficking of the receptor have not yet been elucidated. We demonstrate here that, in nonlymphoid cells, CD46 is constitutively internalized via clathrin-coated pits, traffics to multivesicular bodies, and is recycled to the cell surface. However, cross-linking of CD46 at the cell surface, by either multivalent antibody or by measles virus, induces pseudopodia that engulf the ligand in a process similar to macropinocytosis, and leads to the degradation of cell surface CD46. Thus, we have elucidated two pathways for CD46 internalization, which are regulated by the valence of cross-linking of CD46 and which utilize either clathrin-coated pits or pseudopodial extension. This has important implications for CD46 signaling, antigen presentation, CD46 down-regulation, and engulfment of pathogens. CD46 is a human cell surface receptor that regulates innate and acquired immune function. CD46 is expressed on all cells except red blood cells and is a receptor for the complement components C3b and C4b and for pathogens, including measles virus, Neisseria gonorrhoeae and meningitides, Group A streptococcus, and human herpes virus 6 (1Santoro F. Kennedy P.E. Locatelli G. Malnati M.S. Berger E.A. Lusso P. Cell. 1999; 99: 817-827Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar, 2Okada N. Liszewski M.K. Atkinson J.P. Caparon M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 2489-2493Crossref PubMed Scopus (207) Google Scholar, 3Kallstrom H. Liszewski M.K. Atkinson J.P. Jonsson A.B. Mol. Microbiol. 1997; 25: 639-647Crossref PubMed Scopus (285) Google Scholar, 4Oglesby T.J. Allen C.J. Liszewski M.K. White D.J. Atkinson J.P. J. Exp. Med. 1992; 175: 1547-1551Crossref PubMed Scopus (131) Google Scholar, 5Dorig R.E. Marcil A. Chopra A. Richardson C.D. Cell. 1993; 75: 295-305Abstract Full Text PDF PubMed Scopus (861) Google Scholar, 6Naniche D. Varior-Krishnan G. Cervoni F. Wild T.F. Rossi B. Rabourdin-Combe C. Gerlier D. J. Virol. 1993; 67: 6025-6032Crossref PubMed Google Scholar). Signaling through CD46 affects T cell functions, including increased proliferation of CD3-stimulated cells, suggesting that CD46 might act as a T cell costimulatory molecule (7Zaffran Y. Destaing O. Roux A. Ory S. Nheu T. Jurdic P. Rabourdin-Combe C. Astier A.L. J. Immunol. 2001; 167: 6780-6785Crossref PubMed Scopus (108) Google Scholar, 8Astier A. Trescol-Biemont M.C. Azocar O. Lamouille B. Rabourdin-Combe C. J. Immunol. 2000; 164: 6091-6095Crossref PubMed Scopus (139) Google Scholar); immunosuppression in mice transgenic for specific isoforms of CD46 (9Marie J.C. Kehren J. Trescol-Biemont M.C. Evlashev A. Valentin H. Walzer T. Tedone R. Loveland B. Nicolas J.F. Rabourdin-Combe C. Horvat B. Immunity. 2001; 14: 69-79Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 10Marie J.C. Astier A.L. Rivailler P. Rabourdin-Combe C. Wild T.F. Horvat B. Nat. Immunol. 2002; 3: 659-666Crossref PubMed Scopus (148) Google Scholar); and induction of T-regulatory (Tr1) cells (11Kemper C. Chan A.C. Green J.M. Brett K.A. Murphy K.M. Atkinson J.P. Nature. 2003; 421: 388-392Crossref PubMed Scopus (478) Google Scholar). Signaling through CD46 can also regulate cytokine production in macrophages (12Karp C.L. Wysocka M. Wahl L.M. Ahearn J.M. Cuomo P.J. Sherry B. Trinchieri G. Griffin D.E. Science. 1996; 273: 228-231Crossref PubMed Scopus (485) Google Scholar, 13Hirano A. Yang Z. Katayama Y. Korte-Sarfaty J. Wong T.C. J. Virol. 1999; 73: 4776-4785Crossref PubMed Google Scholar, 14Katayama Y. Hirano A. Wong T.C. J. Virol. 2000; 74: 1252-1257Crossref PubMed Scopus (47) Google Scholar, 15Kurita-Taniguchi M. Fukui A. Hazeki K. Hirano A. Tsuji S. Matsumoto M. Watanabe M. Ueda S. Seya T. J. Immunol. 2000; 165: 5143-5152Crossref PubMed Scopus (75) Google Scholar), and binding to CD46 can influence how foreign antigen is presented to the immune system by MHC 1The abbreviations used are: MHCmajor histocompatibility complexFITCfluorescein isothiocyanatePEphycoerythrinEGFPenhanced green fluorescent proteinPBSphosphate-buffered salineCHOChinese hamster ovary.1The abbreviations used are: MHCmajor histocompatibility complexFITCfluorescein isothiocyanatePEphycoerythrinEGFPenhanced green fluorescent proteinPBSphosphate-buffered salineCHOChinese hamster ovary. Class or D. Trescol-Biemont M.C. Varior-Krishnan G. D. Rabourdin-Combe C. PubMed Scopus Google Scholar, P. Trescol-Biemont M.C. C. Rabourdin-Combe C. Horvat B. J. Immunol. PubMed Scopus Google Scholar, P. Gerlier D. Wild T.F. Rabourdin-Combe C. 1995; PubMed Scopus Google Scholar, D. Trescol-Biemont M.C. Varior-Krishnan G. D. Rabourdin-Combe C. J. Exp. Med. PubMed Scopus Google Scholar, G. Trescol-Biemont M.C. D. Rabourdin-Combe C. Gerlier D. J. Virol. PubMed Google Scholar, Gerlier D. Wild T.F. Rabourdin-Combe C. J. Virol. 1996; PubMed Scopus Google Scholar). CD46 also a in the protection of cells from by as a for the breakdown of C3b and C4b T.J. Allen C.J. Liszewski M.K. White D.J. Atkinson J.P. J. Exp. Med. 1992; 175: 1547-1551Crossref PubMed Scopus (131) Google Scholar). histocompatibility green fluorescent hamster ovary. histocompatibility green fluorescent hamster ovary. of CD46 measles can a down-regulation of CD46 from the cell surface D. Wild T.F. Rabourdin-Combe C. Gerlier D. J. Virol. 1993; 74: PubMed Scopus Google Scholar). This down-regulation is increased to attack and of the cell to measles and affects antigen and through CD46 G. Trescol-Biemont M.C. D. Rabourdin-Combe C. Gerlier D. J. Virol. PubMed Google Scholar, A. S. K. Korte-Sarfaty J. Seya T. S. Wong T.C. J. Virol. 1996; PubMed Google Scholar, S. Hirano A. Wong T.C. J. Virol. 1997; PubMed Google Scholar, R. C.J. U. R. J. J. Virol. 1999; 73: PubMed Google Scholar, J. J. L.M. S. J. Virol. 1996; PubMed Google Scholar, S. C. Rabourdin-Combe C. J. Virol. 1995; PubMed Scopus Google Scholar, J. U. L.M. K. S. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: PubMed Scopus Google Scholar, J. L.M. F. B. J. Virol. 1995; PubMed Google Scholar, L.M. R. J. S. J. Immunol. 1995; 25: PubMed Scopus Google Scholar). is that the of CD46 from the cell surface is important for of the the by which CD46 is internalized has not been elucidated. have that CD46 is not internalized A. G. Liszewski M.K. Atkinson J.P. G. J. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. G. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), has of CD46 by D. Wild T.F. Rabourdin-Combe C. Gerlier D. J. Virol. 1993; 74: PubMed Scopus Google Scholar). of the that CD46 is of importance is that the at the of the in of is important for CD46 down-regulation in to measles S. Hirano A. Wong T.C. J. Virol. 1997; PubMed Google Scholar). the of CD46 on the of measles antigen can by of D. Trescol-Biemont M.C. Varior-Krishnan G. D. Rabourdin-Combe C. PubMed Scopus Google Scholar, D. Trescol-Biemont M.C. Varior-Krishnan G. D. Rabourdin-Combe C. J. Exp. Med. PubMed Scopus Google Scholar). We here the of CD46 and two by CD46 We the implications of these to antigen presentation, CD46 down-regulation, and through CD46. used cells cells B. A.L. M.S. R. 1997; PubMed Scopus (122) Google Scholar), and cells measles cells S. C. Rabourdin-Combe C. J. Virol. 1995; PubMed Scopus Google T cells by in cells from by to at and in human and human in for 6 cells either or in and by cells and cell at in to CD46 Atkinson J.P. T.J. Google T. T. Matsumoto M. Y. H. J. Exp. Med. PubMed Scopus Google P. D. M. D. C.J. J. PubMed Scopus Google and D. Varior-Krishnan G. Cervoni F. Wild T.F. Rossi B. Rabourdin-Combe C. Gerlier D. J. Virol. 1993; 67: 6025-6032Crossref PubMed Google The antibody to CD46 of and and to S. T. T. D.J. J. Immunol. 1992; Google M.S. G. 25: PubMed Scopus Google and or and and The The and The CD46 on either the and and the or the the and the D.J. PubMed Scopus Google Scholar, J. Immunol. 1992; PubMed Scopus Google and the to J. D. Loveland J. 1996; PubMed Scopus Google Scholar). and by the the to of CD46 that all and isoforms and from are of CD46 and in and surface cells either or for on and either or antibody to and internalization, cells in at as a by the of the of internalized surface from the cell surface by at for on and cells and in and for by the of used a antibody to these intracellular antibody internalization, and a antibody to the down-regulation of for and cells at a of or antibody as antibody by in at for on and cells for surface CD46 by by to as and not the or CD46 that the surface antibody and that the antibody not affect the binding of in or or in and at or for to and the R. 1995; Google Scholar), either or antibody to or and in of CD46 cross-linking at the cell surface as except that the antibody to used at CD46 cells the antibody to CD46 not binding to cells, antibody by either or by and antibody to The as by the by J. M.S. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). a The from a used to the and through the The from a used to the and through the at for the and are of at two of and that the of CD46 cell cells and cells all of which similar CD46 either to or to CD46 used in these or cells also antibody to and either or cells to the antibody at and at for or in and in for at in and cells in in in for not to a antibody to the antibody and at at the of to in in and in in by and for at in in in through a of and in on a and and in a cells in or for or at at in on a in and and antibody to and from in and to CD46 binding D. Loveland B. P. M. C. Gerlier D. J. Virol. 2000; PubMed Scopus Google for at in at for and the cell in of and at for at for cells in of to by and of the CD46 and as in B. Loveland M. S. J. 2002; Full Text Full Text PDF PubMed Scopus Google by the and for and CD46 the of cells of antibody to CD46 at at either or for the internalized antibody by or of antibody to CD46 internalized from the surface of cells not from the T cell as by protection from at cells at and that antibody not from the cell surface and CD46 internalized from all cell or from the surface of human or cell by and and and isoforms of CD46 of not The antibody to CD46 cells, and antibody to the to cells not internalized at not that CD46 from the surface of cells not from the surface of on nonlymphoid human cell CD46 blood cell cell cell cell in a CD46 also of and to of CD46 not suggesting that CD46 might a We that, the of CD46 a process not by the not a down-regulation of CD46 at the cell surface. We the antibody the surface of CD46 on cells a for CD46 down-regulation, cells for at cells measles virus S. C. Rabourdin-Combe C. J. Virol. 1995; PubMed Scopus Google Scholar), in surface CD46 on the cells cells the surface of CD46 on cells not by at for antibody internalized not the to on surface CD46 not and the of CD46 surface not to the cells that the of CD46 from the cell surface through is by a in CD46 from intracellular and are the that CD46 is constitutively the cell surface and intracellular CD46 the antibody that been internalized to a the cells CD46 This similar to the of CD46 in these cells suggesting that internalized CD46 might to the of CD46 we a in which the of CD46 the intracellular and trafficking as as by not and of internalized antibody the internalized antibody and red in the and green in that internalized CD46 to the of of CD46. that intracellular CD46 is at in of CD46 that has been internalized from the cell surface. to the of intracellular CD46. cells and to CD46 and which that intracellular CD46 not in the not to the we used the which to the of This is by the which in the J. M.S. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). for a that is through the the intracellular CD46 in cells and green in in the by and red in Thus, at of the CD46 is either in through the or is internalized a in cells, of the intracellular of CD46 and green in in the as internalized CD46 and red in that internalized CD46 traffics to a in the of the not the to is the CD46 by and by A not suggesting that not all of the CD46 in that internalization, CD46 traffics to a at or the CD46 to the of internalized we on to CD46 of multivesicular and multivesicular and in the of This is in and is of the the receptor and which are the D.J. B. Cell. Full Text PDF PubMed Scopus Google Scholar, S. K. G. A. J. Cell. Full Text PDF PubMed Scopus Google Scholar). CD46 via and the receptor traffics to multivesicular via clathrin-coated CD46 a similar cells the antibody to CD46 for at and a antibody to to CD46 in clathrin-coated pits from the cell surface and in internalized clathrin-coated pits for to to through clathrin-coated and to that via which on clathrin-coated pits and pits also either or cells CD46 the antibody not the trafficking of CD46 we and cells and the antibody to CD46. CD46 in the clathrin-coated pits of these cells and in clathrin-coated the not clathrin-coated pits not that the of internalized to CD46 to the of CD46 the of CD46 via clathrin-coated pits is a the of CD46 is to two and which are in all cell J. Immunol. 1992; PubMed Scopus Google Scholar). a that the of CD46 the cell B. Loveland M. S. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). we that of CD46 the of clathrin-coated The in the of the to to and T. B. O. J. 273: Full Text Full Text PDF PubMed Scopus Google Scholar). or not the of the The and CD46 in the system cells and and not of all on in and that expressed that CD46 and via the to CD46 the which is of for two to the to important for of for via clathrin-coated pits, and for to the multivesicular L.M. 2003; PubMed Scopus Google Scholar). has been to for the down-regulation of CD46 in cells constitutively the measles virus, and has been that to on of CD46 S. Hirano A. Wong T.C. J. Virol. 1997; PubMed Google Scholar). that the of CD46 in clathrin-coated pits via in a similar to the of is the that CD46 and red in and the receptor and green in are internalized to a similar CD46 in cells not as as in cells and the However, the the of the and the of in that not in CD46 and Thus, CD46 the clathrin-coated molecule and is constitutively internalized via clathrin-coated pits, traffics to a multivesicular the and is recycled to the cell surface. This process of of CD46 the of these we that of CD46 the cells that not been by A of cells that been or a antibody to CD46 to the antibody and of cells in the trafficking of to intracellular the and the of the cell by cells used to the internalized CD46 the CD46. CD46 internalized to the intracellular as the CD46 and a the cell red and green that been internalized cross-linking and antibody to in that the intracellular CD46 the red which not the green the antibody to which also to multivalent a to that by not the to CD46 are multivalent or virus we cross-linking CD46 might have the as cross-linking CD46 We the of by cells cells the measles virus cells have been used to the of measles virus on CD46 and the of the measles virus in CD46 down-regulation S. C. Rabourdin-Combe C. J. Virol. 1995; PubMed Scopus Google Scholar). of cells CD46 cells a of CD46 similar to that either or the of in cells in the intracellular of CD46 D. Wild T.F. Rabourdin-Combe C. Gerlier D. J. Virol. 1993; 74: PubMed Scopus Google Scholar). that CD46 can by two pathways and that the is by the of cross-linking of CD46. CD46 via to CD46 the surface of CD46 on cells that been for (i) (ii) cells, (iii) the antibody to CD46 or (iv) the antibody to CD46. the down-regulation of CD46 surface and on CD46 surface (iv) in a of surface of CD46 similar to that Thus, cross-linking of CD46 by either multivalent antibody or by multivalent measles which through in down-regulation of CD46. which through not in the down-regulation of CD46. that the of by the valence of we in which the antibody to CD46 at the the valence of cross-linking of antibody to of antibody not CD46 down-regulation of antibody in a in the down-regulation of CD46 and not to a of binding or internalization, binding of the antibody in all not and antibody internalized and from in all the antibody on down-regulation, the of the to down-regulation the antibody internalized not that of antibody to CD46 that valence binding not the CD46 is internalized via and is not of antibody multivalent cross-linking and and the down-regulation of CD46. of CD46 via in of CD46 from the trafficking of CD46 through that the of CD46 in multivesicular is in the cell surface CD46 and that CD46 from multivesicular is recycled to the cell surface. the down-regulation of surface CD46 that we and R. C.J. U. R. J. J. Virol. 1999; 73: PubMed Google Scholar, J. J. L.M. S. J. Virol. 1996; PubMed Google Scholar, S. C. Rabourdin-Combe C. J. Virol. 1995; PubMed Scopus Google Scholar, D. Wild T.F. Rabourdin-Combe C. Gerlier D. J. Virol. 1993; 74: PubMed Scopus Google Scholar, J. M. J. R. Wild T.F. R. J. Virol. 1996; PubMed Google cross-linking by a in the CD46 in multivesicular we the of cross-linking on the of CD46 of cells the antibody CD46 by suggesting that the cell surface and the intracellular of CD46 been We the of surface cross-linking on the intracellular cells cells measles for the and by the of cell surface CD46 and the of intracellular CD46 However, and CD46 on the cell surface and in the that cross-linking of CD46 at the cell surface not affects cell surface CD46 also CD46 from in multivesicular A for is that CD46 multivesicular and the cell surface, that CD46 that has constitutively internalized via to the cell surface, can and through to CD46 via the of used to the of of cells CD46 the antibody not in the of clathrin-coated CD46 pseudopodia or which to the CD46 in of in CD46 internalized these of by or by and antibody to This of not for that not been and not the multivesicular not that CD46 internalized via in that the not multivesicular The of the pseudopodia and the of the similar to for macropinocytosis, a process by in various cell Y. J. 2001; PubMed Scopus Google Scholar, N. J. 1996; PubMed Scopus Google Scholar, C. 1995; PubMed Scopus Google Scholar). that CD46 via the induction of pseudopodia and not clathrin-coated We by measles virus cells the of measles virus for and to that the virus in the process of the cell from the measles virus in in the of and not on cells that not that specific binding to CD46 for of virus that CD46 binding a to the of not and cells of pseudopodia of the cell from the Thus, cross-linking of CD46 by or measles virus can the production of the that measles virus that or might via The for measles is through pathways to virus from the cell surface. virus is to we not However, of that of a and measles virus as cells of virus not pseudopodia and to in the process of by that the cross-linking of CD46 at the cell surface by antibody or measles virus a process similar to We here the of the mechanisms by which CD46 is internalized and that internalized CD46 can of two intracellular pathways the valence of ligand binding at the cell surface and the cell nonlymphoid cells, CD46 constitutively from the cell surface via clathrin-coated pits, to multivesicular bodies, and is recycled to the cell surface However, cross-linking of CD46 at the cell surface can to a which is of clathrin-coated pits, leads to and This in nonlymphoid cells, as and in cells, as by the CD46 down-regulation in cells cells S. C. Rabourdin-Combe C. J. Virol. 1995; PubMed Scopus Google not pathways have a of implications for the of CD46. CD46 and and here for CD46 is a of either the or a of the of by the receptor or for antigen by C. J. 1999; Full Text Full Text PDF PubMed Scopus Google The of CD46 to in the regulation of antigen The multivesicular to which CD46 constitutively traffics are similar to the antigen for Class to Class MHC J.M. C. Nature. PubMed Scopus Google measles virus has been Class MHC in the of a cell system M. H. J. A. D. J. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar, J.M. J.M. C.J. C. 2001; PubMed Scopus Google Scholar), and CD46 and has been Class MHC Immunol. PubMed Scopus Google Scholar), suggesting a the of CD46 can affect the of either by the of or by to by Class D. Trescol-Biemont M.C. Varior-Krishnan G. D. Rabourdin-Combe C. PubMed Scopus Google Scholar, P. Trescol-Biemont M.C. C. Rabourdin-Combe C. Horvat B. J. Immunol. PubMed Scopus Google Scholar, P. Gerlier D. Wild T.F. Rabourdin-Combe C. 1995; PubMed Scopus Google Scholar, D. Trescol-Biemont M.C. Varior-Krishnan G. D. Rabourdin-Combe C. J. Exp. Med. PubMed Scopus Google Scholar, Gerlier D. Wild T.F. Rabourdin-Combe C. J. Virol. 1996; PubMed Scopus Google Scholar). However, the of have a presentation, can also the of antigen via MHC and can affect the of via Class or Class P. P. A. S. J. Immunol. 1999; Google Scholar, C. M. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. G. J. J. Immunol. 2000; 165: PubMed Scopus Google Scholar). The of two pathways for CD46 a from which to the influence of cross-linking on antigen presentation, by the of and and the of of the two pathways on antigen also the that CD46 a in the for on and and of signaling through a cell surface receptor is to the of the receptor P. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). signaling from is by the and degradation of the the signaling of the receptor is by S. J. Sci. 2001; PubMed Google Scholar). Signaling through CD46 is by receptor cross-linking and A. Trescol-Biemont M.C. Azocar O. Lamouille B. Rabourdin-Combe C. J. Immunol. 2000; 164: 6091-6095Crossref PubMed Scopus (139) Google Scholar, C. Chan A.C. Green J.M. Brett K.A. Murphy K.M. Atkinson J.P. Nature. 2003; 421: 388-392Crossref PubMed Scopus (478) Google Scholar, C.L. Wysocka M. Wahl L.M. Ahearn J.M. Cuomo P.J. Sherry B. Trinchieri G. Griffin D.E. Science. 1996; 273: 228-231Crossref PubMed Scopus (485) Google and is to The that leads to the down-regulation of CD46 that regulates CD46 the here and the in T cells by CD46 signaling (7Zaffran Y. Destaing O. Roux A. Ory S. Nheu T. Jurdic P. Rabourdin-Combe C. Astier A.L. J. Immunol. 2001; 167: 6780-6785Crossref PubMed Scopus (108) Google are the that of the in CD46 signaling are also in trafficking and cell (7Zaffran Y. Destaing O. Roux A. Ory S. Nheu T. Jurdic P. Rabourdin-Combe C. Astier A.L. J. Immunol. 2001; 167: 6780-6785Crossref PubMed Scopus (108) Google Scholar, 8Astier A. Trescol-Biemont M.C. Azocar O. Lamouille B. Rabourdin-Combe C. J. Immunol. 2000; 164: 6091-6095Crossref PubMed Scopus (139) Google Scholar, B. Loveland M. S. J. 2002; Full Text Full Text PDF PubMed Scopus Google and that a of CD46 signaling is to the cell The of of CD46 in is of which is constitutively internalized and recycled to the cell surface in cell and in and macrophages is from in cell by binding of A. N. S. M. J. Immunol. PubMed Scopus Google Scholar, C. S. A. K. M. Mol. Cell. 1999; PubMed Scopus Google Scholar). T cell of of and of the receptor A. M. J. Exp. Med. 1993; PubMed Scopus Google Scholar). CD46 also including Atkinson J.P. M. J. 2002; PubMed Scopus Google Scholar, G. Liszewski M.K. Chan A.C. Atkinson J.P. J. Immunol. 2000; 164: PubMed Scopus Google Scholar), and to a similar the of CD46. CD46 as a of that the cross-linking of CD46 is not a of internalization, as might have been CD46 to a of the of or which to CD46 of in The of these pseudopodia that for macropinocytosis, a process for of and C. M. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). can in cell by as and and Y. J. 2001; PubMed Scopus Google Scholar, T. K. D. J. J. J. Sci. 2002; PubMed Google Scholar, S. A. J. Mol. Cell. 2000; PubMed Scopus Google Scholar). We that the down-regulation of CD46 the induction of and of CD46 can by measles measles expressed on cells, complement M. to and a antibody not by or used at to R. C.J. U. R. J. J. Virol. 1999; 73: PubMed Google and S. C. Rabourdin-Combe C. J. Virol. 1995; PubMed Scopus Google Scholar, and M. The molecular in the of CD46 have been here that the valence of binding can and these that down-regulation of CD46 is by of CD46 Thus, either measles virus which are Wild T.F. J. Virol. 1993; 74: PubMed Scopus Google or a the by antibody and This engulfment of these we here that measles virus can similar of pseudopodia in cells, which for of cell from the of the virus the at can from these that also cells The pseudopodia by cross-linking and measles virus are similar to by the binding of N. to human cells C. S. J. Sci. 2002; Google Scholar). The receptor is not for the induction of pseudopodia Neisseria binding S. J. 2001; PubMed Scopus Google Scholar). CD46 can to the of N. H. Liszewski M.K. Atkinson J.P. Jonsson A.B. Mol. Microbiol. 1997; 25: 639-647Crossref PubMed Scopus (285) Google and the A. P. B. H. T. B. R. Jonsson A.B. Science. 2003; PubMed Scopus Google Scholar). that CD46 might the of Neisseria by Thus, is that CD46 can the of multivalent to the of multivalent The induction of pseudopodia the of Neisseria to cells, the of the of CD46 is H. D. B. Liszewski M.K. Atkinson J.P. Jonsson A.B. Microbiol. 2001; 3: PubMed Scopus Google Scholar). The of cross-linking CD46 on and can to is from these that CD46 cross-linking induces a in the by which the receptor is internalized and that the down-regulation of CD46. The here that CD46 can internalized by two either clathrin-coated pits or The of CD46 internalized via is to influence antigen of complement regulation CD46 at the cell and through CD46. these for the a for CD46 in the engulfment of or We Seya and for the and and and for