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J. Biol. Chem., Vol. 278, Issue 47, 46927-46937, November 21, 2003

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

Blessing Crimeen-Irwin, Sarah Ellis, Dale Christiansen¶||**, Mandy J. Ludford-Menting, Julie Milland¶, Marc Lanteri¶, Bruce E. Loveland¶, Denis Gerlier||, and Sarah M. Russell

From the Peter MacCallum Cancer Centre, Trescowthick Research Laboratories, St. Andrew's Place, East Melbourne, Victoria 3002, Australia, ^¶The Austin Research Institute, Austin Health, Studley Road, Heidelberg, Victoria 3084, Australia, and ^||Immunity et Infections Virales, Institut Fédératif Laennec, CNRS-UCBL UMR5537, 69372 Lyon Cedex 08, France

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.

Received for publication, July 29, 2003 , and in revised form, August 29, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by an Australian Postgraduate Research Award.

^** Supported by a National Health and Medical Research Council Howard Florey Centenary Research Fellowship.

Supported by a Wellcome Senior Research Fellowship in Medical Research. To whom correspondence should be addressed. Tel.: 613-9656-3727; Fax: 613-9656-1411; E-mail: sarah.russell{at}petermac.org.

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