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J. Biol. Chem., Vol. 281, Issue 44, 33352-33362, November 3, 2006

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Modulation of the Cellular Cholesterol Level Affects Shedding of the Type XIII Collagen Ectodomain^*

Timo Väisänen, Marja-Riitta Väisänen, and Taina Pihlajaniemi¹

From the Collagen Research Unit, Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology and the Department of Pathology, University of Oulu, 90014 Oulu, Finland

Type XIII collagen is a transmembrane protein that also exists as a soluble extracellular variant because of ectodomain shedding by proprotein convertases. Because ectodomain shedding in a growing number of transmembrane proteins has recently been shown to be dependent on their localization in cholesterol-enriched detergent-resistant membrane microdomains, this work aimed at analyzing this aspect of type XIII collagen ectodomain processing. In HT-1080 cells type XIII collagen and its cleaving proprotein convertase furin localized partially in detergent-resistant cholesterol-containing membrane microdomains. Disruption of these domains by lowering either the level or availability of the cellular cholesterol reduced ectodomain shedding, implying that, in such membrane domains correct cholesterol level is important for the regulation of type XIII collagen ectodomain processing. In addition, we show here that ectodomain of type XIII collagen is also shed intracellularly. HT-1080 cells released vesicles from the Golgi apparatus, which contained only the cleaved variant. Intracellular processing and the subsequent entry of the cleaved ectodomain into the vesicles was totally blocked by inhibition of the proprotein convertase function by cell-permeable chloromethylketone, but not with cell-impermeable 1-antitrypsin Portland. This supports the hypothesis of type XIII collagen ectodomain also being cleaved intracellularly in the Golgi and suggests that the intracellular cleavage may act as a gating event in the vesicle-mediated ectodomain secretion.

Received for publication, June 20, 2006

^* This work was supported by European Commission Grant 504743 and by the Sigrid Jusélius Foundation and the Academy of Finland Centre of Excellence Programme. 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: Dept. of Medical Biochemistry and Molecular Biology, University of Oulu, P.O. Box 5000, FIN-90014 Oulu, Finland. Tel.: 358-8-5375800; Fax: 358-8-5375810; E-mail: taina.pihlajaniemi{at}oulu.fi.

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