Abstract
Meprin β is a dimeric type I transmembrane protein and acts as an ectodomain sheddase at the cell surface. It has been shown that meprin β cleaves the amyloid precursor protein (APP), thereby releasing neurotoxic amyloid β peptides and implicating a role of meprin β in Alzheimer’s disease. In order to identify non-proteolytic regulators of meprin β, we performed a split ubiquitin yeast two-hybrid screen using a small intestinal cDNA library. In this screen we identified tetraspanin 8 (TSPAN8) as interaction partner for meprin β. As several members of the tetraspanin family were described to interact with metalloproteases thereby affecting their localization and/or activity, we hypothesized similar functions of TSPAN8 in the regulation of meprin β. We employed cell biological methods to confirm direct binding of TSPAN8 to meprin β. Surprisingly, we did not observe an effect of TSPAN8 on the catalytic activity of meprin β nor on the specific cleavage of its substrate APP. However, both proteins were identified as present in tetraspanin-enriched microdomains. Therefore we hypothesize that TSPAN8 might be important for the orchestration of meprin β at the cell surface with impact on certain proteolytic processes that have to be further identified.
Acknowledgments
The authors thank Björn Rabe (Kiel, Germany) for providing the CD9 antibody, Xavier Gomis-Rüth (Barcelona, Spain) for the pdb file of membrane-bound dimeric meprin β and Yves Jacob (Paris, France) as well as Jörg Müller (Jena, Germany) for providing plasmids. This work was supported by the SFB877 ‘Proteolysis as a Regulatory Event in Pathophysiology’ (project A9), grant BE 4086/2-1 (to C.B.-P.), grant PI 379/6-1 (to C.U.P.) and SFB841 (project C1, to D.S.-A.). W.A. is supported by KULeuven (C16/15/073), VIB, SAO (S#14017) and the federal government (IAP P7/16).
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