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Tetraspanin 8 is an interactor of the metalloprotease meprin β within tetraspanin-enriched microdomains
Abstract:
Meprin β is a dimeric type I transmembrane protein and acts as an ectodomain sheddase at the cell surface. It was 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. Since 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 being 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.
Insights
Tetraspanin 8 (TSPAN8) interacts with meprin β, an enzyme implicated in Alzheimer's disease. While TSPAN8 does not affect meprin β activity or APP cleavage, it may regulate meprin β localization at the cell surface.
Area of Science:
- Biochemistry
- Cell Biology
- Neuroscience
Background:
- Meprin β is a cell surface ectodomain sheddase implicated in Alzheimer's disease via amyloid precursor protein (APP) cleavage.
- Identifying non-enzymatic regulators of meprin β is crucial for understanding its role in disease.
Purpose of the Study:
- To identify non-proteolytic regulators of meprin β.
- To investigate the interaction between tetraspanin 8 (TSPAN8) and meprin β.
Main Methods:
- Split ubiquitin yeast two-hybrid screen using a small intestinal cDNA library.
- Cell biological methods to confirm protein binding.
- Analysis of meprin β catalytic activity and APP cleavage.
- Localization studies within tetraspanin-enriched microdomains.
Main Results:
- TSPAN8 was identified as an interaction partner of meprin β.
- Direct binding between TSPAN8 and meprin β was confirmed.
- TSPAN8 did not alter meprin β's catalytic activity or its cleavage of APP.
- Both meprin β and TSPAN8 were found in tetraspanin-enriched microdomains.
Conclusions:
- TSPAN8 interacts with meprin β but does not modulate its enzymatic activity or substrate cleavage.
- TSPAN8 may play a role in the cell surface localization and organization of meprin β.
- Further research is needed to elucidate TSPAN8's impact on meprin β-mediated proteolytic processes.
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