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Tetraspanin 3: A central endocytic membrane component regulating the expression of ADAM10, presenilin and the amyloid precursor protein
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Accepted Version
Date
2016-11-03
Authors
Seipold, Lisa
Damme, Markus
Prox, Johannes
Rabe, Bjorn
Kasparek, Petr
Sedlacek, Radislav
Altmeppen, Hermann
Willem, Michael
Boland, Barry
Glatzel, Markus
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Published Version
Abstract
Despite 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.
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Keywords
ADAM10 , Tetraspanin , APP , Presenilin
Citation
Seipold, 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.2016.11.003