Tetraspanin 3: A central endocytic membrane component regulating the expression of ADAM10, presenilin and the amyloid precursor protein

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dc.check.date2017-11-03
dc.check.infoAccess to this item is restricted until 12 months after publication by the request of publisher.en
dc.contributor.authorSeipold, Lisa
dc.contributor.authorDamme, Markus
dc.contributor.authorProx, Johannes
dc.contributor.authorRabe, Bjorn
dc.contributor.authorKasparek, Petr
dc.contributor.authorSedlacek, Radislav
dc.contributor.authorAltmeppen, Hermann
dc.contributor.authorWillem, Michael
dc.contributor.authorBoland, Barry
dc.contributor.authorGlatzel, Markus
dc.contributor.authorSaftig, Paul
dc.contributor.funderDeutsche Forschungsgemeinschaften
dc.contributor.funderStiftung VERUMen
dc.contributor.funderFederaal Wetenschapsbeleiden
dc.contributor.funderAkademie Věd České Republikyen
dc.contributor.funderHans und Ilse Breuer-Stiftung, Germany (Hans und Ilse Breur Foundation, Alzheimer Research)en
dc.contributor.funderCreutzfeldt-Jakob Disease Foundation Inc. United Statesen
dc.date.accessioned2016-11-14T11:44:23Z
dc.date.available2016-11-14T11:44:23Z
dc.date.issued2016-11-03
dc.date.updated2016-11-14T10:30:53Z
dc.description.abstractDespite existing knowledge about the role of the A Disintegrin and Metalloproteinase 10 (ADAM10) as the α-secretase involved in the non-amyloidogenic processing of the amyloid precursor protein (APP) and Notch signalling we have only limited information about its regulation. In this study, we have identified ADAM10 interactors using a split ubiquitin yeast two hybrid approach. Tetraspanin 3 (Tspan3), which is highly expressed in the murine brain and elevated in brains of Alzheimer's disease (AD) patients, was identified and confirmed to bind ADAM10 by co-immunoprecipitation experiments in mammalian cells in complex with APP and the γ-secretase protease presenilin. Tspan3 expression increased the cell surface levels of its interacting partners and was mainly localized in early and late endosomes. In contrast to the previously described ADAM10-binding tetraspanins, Tspan3 did not affect the endoplasmic reticulum to plasma membrane transport of ADAM10. Heterologous Tspan3 expression significantly increased the appearance of carboxy-terminal cleavage products of ADAM10 and APP, whereas N-cadherin ectodomain shedding appeared unaffected. Inhibiting the endocytosis of Tspan3 by mutating a critical cytoplasmic tyrosine-based internalization motif led to increased surface expression of APP and ADAM10. After its downregulation in neuroblastoma cells and in brains of Tspan3-deficient mice, ADAM10 and APP levels appeared unaltered possibly due to a compensatory increase in the expression of Tspans 5 and 7, respectively. In conclusion, our data suggest that Tspan3 acts in concert with other tetraspanins as a stabilizing factor of active ADAM10, APP and the γ-secretase complex at the plasma membrane and within the endocytic pathway.en
dc.description.sponsorshipDeutsche Forschungsgemeinschaft (DFG Sonderforschungsbereich 877 (projects A3, A12)); Stiftung VERUM (VERUM foundation); Alzheimer Research Price of the Breuer Foundation; Federaal Wetenschapsbeleid (Belgian Federal Science Policy Office Interuniversity Attraction Poles Program IUAP P7/16); The CreutzfeldJacob Disease Foundation, Inc; Akademie Věd České Republiky (Academy of Sciences of the Czech Republic (RVO 68378050), LM2011032 and LM2015040 (MEYS))en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationSeipold, L., Damme, M., Prox, J., Rabe, B., Kasparek, P., SedlaceK, R., Altmeppen, H., Willem, M., Boland, B., GlatzeL, M. and Saftig, P. (2016) ‘Tetraspanin 3: A central endocytic membrane component regulating the expression of ADAM10, presenilin and the amyloid precursor protein’, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1864(1), pp. 217-230. doi: 10.1016/j.bbamcr.2016.11.003en
dc.identifier.doi10.1016/j.bbamcr.2016.11.003
dc.identifier.endpage230
dc.identifier.issn0006-3002
dc.identifier.issued1
dc.identifier.journaltitleBiochimica et Biophysica Acta (BBA) - Molecular Cell Researchen
dc.identifier.startpage217
dc.identifier.urihttps://hdl.handle.net/10468/3271
dc.identifier.volume1864
dc.language.isoenen
dc.publisherElsevieren
dc.rights© 2016, Elsevier B.V. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectADAM10en
dc.subjectTetraspaninen
dc.subjectAPPen
dc.subjectPresenilinen
dc.titleTetraspanin 3: A central endocytic membrane component regulating the expression of ADAM10, presenilin and the amyloid precursor proteinen
dc.typeArticle (peer-reviewed)en
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