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Ullrich, S.* ; Münch, A.* ; Neumann, S.* ; Kremmer, E. ; Tatzelt, J.* ; Lichtenthaler, S.F.*

The novel membrane protein TMEM59 modulates complex glycosylation, cell surface expression, and secretion of the amyloid precursor protein.

J. Biol. Chem. 285, 20664-20674 (2010)

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Open Access Green as soon as Postprint is submitted to ZB.

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Ectodomain shedding of the amyloid precursor protein (APP) by the two proteases alpha- and beta-secretase is a key regulatory event in the generation of the Alzheimer disease amyloid beta peptide (Abeta). At present, little is known about the cellular mechanisms that control APP shedding and Abeta generation. Here, we identified a novel protein, transmembrane protein 59 (TMEM59), as a new modulator of APP shedding. TMEM59 was found to be a ubiquitously expressed, Golgi-localized protein. TMEM59 transfection inhibited complex N- and O-glycosylation of APP in cultured cells. Additionally, TMEM59 induced APP retention in the Golgi and inhibited Abeta generation as well as APP cleavage by alpha- and beta-secretase cleavage, which occur at the plasma membrane and in the endosomes, respectively. Moreover, TMEM59 inhibited the complex N-glycosylation of the prion protein, suggesting a more general modulation of Golgi glycosylation reactions. Importantly, TMEM59 did not affect the secretion of soluble proteins or the alpha-secretase like shedding of tumor necrosis factor alpha, demonstrating that TMEM59 did not disturb the general Golgi function. The phenotype of TMEM59 transfection on APP glycosylation and shedding was similar to the one observed in cells lacking conserved oligomeric Golgi (COG) proteins COG1 and COG2. Both proteins are required for normal localization and activity of Golgi glycosylation enzymes. In summary, this study shows that TMEM59 expression modulates complex N- and O-glycosylation and suggests that TMEM59 affects APP shedding by reducing access of APP to the cellular compartments, where it is normally cleaved by alpha- and beta-secretase.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords N-linked glycosylation; Trans-golgi network; Alzheimers-disease; Gamma-secretase; Alpha-Secretase; Beta-secretase; Intramembrane proteolysis; Mediated endocytosis; Converting-enzyme; Cleaving enzyme

ISSN (print) / ISBN 0021-9258

e-ISSN 1083-351X

Journal Journal of Biological Chemistry, The

Quellenangaben Volume: 285, Issue: 27, Pages: 20664-20674

Publisher American Society for Biochemistry and Molecular Biology

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Molecular Immunology (IMI)