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J. Biol. Chem., Vol. 281, Issue 30, 21369-21376, July 28, 2006

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ADAM10-mediated Release of Complement Membrane Cofactor Protein during Apoptosis of Epithelial Cells^*

From the Departments of Pathology and Virology, Haartman Institute and Biomedicum Helsinki, University of Helsinki and Helsinki University Hospital, Helsinki 00014, Finland

Membrane cofactor protein CD46 controls complement activation on cells, is a receptor for several pathogens, and modulates immune responses by affecting CD8⁺ T cells. Cells can release CD46 in an intact form on membrane vesicles and in a truncated form by a metalloproteolytic cleavage. The mechanism of shedding and its relationship to cell physiology has remained unclear. We have found using RNA interference analysis that a disintegrin and metalloproteinase (ADAM) 10 is responsible for the regulated shedding of the ectodomain of CD46 in apoptotic cells. The shedding of CD46 was initiated with staurosporine and UVB. Exposure of cell cultures to either UVB or staurosporine resulted in changes of cell morphology and detachment of cells from their matrices within 8-24 h. During this process CD46 was released both in apoptotic vesicles (vCD46) and proteolytically (sCD46) into the medium. Both the metalloproteinase inhibitor GM6001 and RNA interference of ADAM10 completely prevented the release of sCD46 and increased the expression of vCD46 on HaCaT cell vesicles, suggesting that ADAM10 releases sCD46 from the apoptotic vesicles. To explore whether the release of sCD46 is associated with apoptosis we analyzed the effects of caspase inhibitors. As expected, the inhibition of caspase activity attenuated the characteristic features of apoptosis and also decreased the release of sCD46. Our results reveal ADAM10 as an important regulator of CD46 expression during apoptosis. The ADAM10-mediated release of CD46 from apoptotic vesicles may represent a form of strategy to allow restricted complement activation to deal with modified self.

Received for publication, March 3, 2006 , and in revised form, May 24, 2006.

^* This work was supported by the Academy of Finland, Biocentrum Helsinki, Finnish Cancer Foundation, the Finnish Cultural Foundation, Helsinki University Hospital Fund, Sigrid Juselius Foundation, Novo Nordisk Foundation, TEKES (Finnish Funding Agency for Technology and Innovation), and the University of Helsinki. 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.

¹ To whom correspondence should be addressed: Biomedicum A506b, P. O. Box 63 (Haartmaninkatu 8), FIN-00014 University of Helsinki, Helsinki, Finland. Tel.: 358-9-19125567; Fax: 358-9-19125610; E-mail: Juha.Hakulinen{at}helsinki.fi.

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