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

Abstract

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. 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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. 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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. 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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