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J. Biol. Chem., Vol. 281, Issue 6, 3698-3710, February 10, 2006

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Lysosomal Sialidase (Neuraminidase-1) Is Targeted to the Cell Surface in a Multiprotein Complex That Facilitates Elastic Fiber Assembly^*

Aleksander Hinek¹, Alexey V. Pshezhetsky^¶, Mark von Itzstein^||, and Barry Starcher^**

From the Cardiovascular Research Program, The Hospital for Sick Children, and the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada, the ^¶Department of Medical Genetics, Sainte-Justine Hospital, and the Departments of Pediatrics and Biochemistry, University of Montreal, Montreal, Quebec H3T 1C5, Canada, the ^||Institute for Glycomics, Griffith University, Queensland 9726, Australia, and the ^**University of Texas Health Center, Tyler, Texas 75708

We have established previously that the 67-kDa elastin-binding protein (EBP), identical to the spliced variant of -galactosidase, acts as a recyclable chaperone that facilitates secretion of tropoelastin. (Hinek, A., Keeley, F. W., and Callahan, J. W. (1995) Exp. Cell Res. 220, 312-324). We now demonstrate that EBP also forms a cell surface-targeted molecular complex with protective protein/cathepsin A and sialidase (neuraminidase-1), and provide evidence that this sialidase activity is a prerequisite for the subsequent release of tropoelastin. We found that treatment with sialidase inhibitors repressed assembly of elastic fibers in cultures of human skin fibroblasts, aortic smooth muscle cells, and ear cartilage chondrocytes and caused impaired elastogenesis in developing chick embryos. Fibroblasts derived from patients with congenital sialidosis (primary deficiency of neuraminidase-1) and galactosialidosis (secondary deficiency of neuraminidase-1) demonstrated impaired elastogenesis, which could be reversed after their transduction with neuraminidase-1 cDNA or after treatment with bacterial sialidase, which has a similar substrate specificity to human neuraminidase-1. We postulate that neuraminidase-1 catalyzes removal of the terminal sialic acids from carbohydrate chains of microfibrillar glycoproteins and other adjacent matrix glycoconjugates, unmasking their penultimate galactosugars. In turn, the exposed galactosugars interact with the galectin domain of EBP, thereby inducing the release of transported tropoelastin molecules and facilitating their subsequent assembly into elastic fibers.

Received for publication, August 8, 2005 , and in revised form, November 15, 2005.

^* This work was supported by Canadian Institutes of Health Research Grant PG 13920 (to A. H.) and Grant MT-38107 (to A. V. P.) and by Heart and Stroke Foundation of Ontario Grant NA 4381 and Career Investigator Award CI 4198 (to A. H.). 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: Cardiovascular Research Program, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-5918; Fax: 416-813-7480; E-mail: alek.hinek{at}sickkids.ca.

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