MCB Accepts, published online ahead of print on 2 November 2009

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Mol. Cell. Biol. doi:10.1128/MCB.01143-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Impaired lysosomal trimming of N-linked oligosaccharides leads to hyperglycosylation of native lysosomal proteins in mannosidosis mice

Markus Damme, Willy Morelle, Bernhard Schmidt, Claes Andersson, Jens Fogh, Jean-Claude Michalski, and Torben Lübke^*

Abt. Biochemie II, Georg-August Universität Göttingen, Humboldtallee 23, 37073 Göttingen, Germany; Unité Mixte de Recherche CNRS/USTL 8576, Glycobiologie Structurale et Fonctionelle, IFR 147, Bâtiment C9, Université des Sciences et Technologies de Lille 1, 59655 Villeneuve d'Ascq, France, Zymenex A/S, Roskildevej 12C, 3400 Hillerød, Denmark

^* To whom correspondence should be addressed. Email: tluebke{at}gwdg.de.

-mannosidosis is caused by the genetic defect of the lysosomal -D-mannosidase (LAMAN) which is involved in the breakdown of free -linked mannose-containing oligosaccharides originating from glycoproteins with N-linked glycans and thus manifests itself in an extensive storage of mannose-containing oligosaccharides. Here we demonstrate in a -mannosidosis mouse model that native lysosomal proteins exhibit elongated N-linked oligosaccharides as shown by 2-D DIGE, deglycosylation assays and mass spectrometry. The analysis of cathepsin B derived oligosaccharides revealed a hypermannosylation of glycoproteins in -mannosidosis mice as indicated by the predominance of extended Man3GlcNAc2 oligosaccharides. Treatment with recombinant human -mannosidase partially corrected the hyperglycosylation of lysosomal proteins in vivo and in vitro. These data clearly demonstrate that LAMAN is not only involved in the lysosomal catabolism of free oligosaccharides but also in the trimming of asparagine-linked oligosaccharides on native lysosomal proteins.