Tetraspanin 8 is an interactor of the metalloprotease meprin β within tetraspanin-enriched microdomains

Schmidt, Frederike; Müller, Miryam; Prox, Johannes; Arnold, Philipp; Schönherr, Caroline; Tredup, Claudia; Minder, Petra; Ebsen, Henriette; Janßen, Ottmar; Annaert, Wim; Pietrzik, Claus U.; Schmidt-Arras, Dirk; Sterchi, Erwin E.; Becker‐Pauly, Christoph

doi:10.1515/hsz-2016-0126

Cited by 13 publications

(9 citation statements)

References 40 publications

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“…Recent studies demonstrated that ADAM10 localization and maturation is influenced by tetraspanins (TSPANs), building microdomains of protein clusters at the cell surface (Prox et al, 2012). In a yeast-two-hybrid approach TSPAN8 was identified as an interaction partner of meprin β, which was further proven by split-RFP and luciferase complementation assays (Schmidt et al, 2016). It was further demonstrated that APP together with meprin β is located in TSPAN8 enriched microdomains.…”

Section: Localizationmentioning

confidence: 99%

The Metalloprotease Meprin β Is an Alternative β-Secretase of APP

Becker‐Pauly

Pietrzik

2017

Front. Mol. Neurosci.

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The membrane bound metalloprotease meprin β is important for collagen fibril assembly in connective tissue formation and for the detachment of the intestinal mucus layer for proper barrier function. Recent proteomic studies revealed dozens of putative new substrates of meprin β, including the amyloid precursor protein (APP). It was shown that APP is cleaved by meprin β in distinct ways, either at the β-secretase site resulting in increased levels of Aβ peptides, or at the N-terminus releasing 11 kDa, and 20 kDa peptide fragments. The latter event was discussed to be rather neuroprotective, whereas the ectodomain shedding of APP by meprin β reminiscent to BACE-1 is in line with the amyloid hypothesis of Alzheimer's disease, promoting neurodegeneration. The N-terminal 11 kDa and 20 kDa peptide fragments represent physiological cleavage products, since they are found in human brains under different diseased or non-diseased states, whereas these fragments are completely missing in brains of meprin β knock-out animals. Meprin β is not only a sheddase of adhesion molecules, such as APP, but was additionally demonstrated to cleave within the prodomain of ADAM10. Activated ADAM10, the α-secretase of APP, is then able to shed meprin β from the cell surface thereby abolishing the β-secretase activity. All together meprin β seems to be a novel player in APP processing events, even influencing other enzymes involved in APP cleavage.

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Section: Localizationmentioning

confidence: 99%

The Metalloprotease Meprin β Is an Alternative β-Secretase of APP

Becker‐Pauly

Pietrzik

2017

Front. Mol. Neurosci.

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“…In regards to β-secretase cleavage, no direct interaction of tetraspanins with the β-secretase BACE1 has been reported. The metalloprotease Meprin β, which cleaves APP in a manner similar to BACE1 (Bien et al, 2012), interacts with Tspan8 and resides together with APP in TEMs (Schmidt et al, 2016). However, Tspan8 had no impact on the proteolytic activity of Meprin β towards APP.…”

Section: Tetraspanins As a Part Of A Multi-secretase Complexmentioning

confidence: 99%

The Emerging Role of Tetraspanins in the Proteolytic Processing of the Amyloid Precursor Protein

Seipold

Säftig

2016

Front. Mol. Neurosci.

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Tetraspanins are a family of ubiquitously expressed and conserved proteins, which are characterized by four transmembrane domains and the formation of a short and a large extracellular loop (LEL). Through interaction with other tetraspanins and transmembrane proteins such as growth factors, receptors and integrins, tetraspanins build a wide ranging and membrane spanning protein network. Such tetraspanin-enriched microdomains (TEMs) contribute to the formation and stability of functional signaling complexes involved in cell activation, adhesion, motility, differentiation, and malignancy. There is increasing evidence showing that the tetraspanins also regulate the proteolysis of the amyloid precursor protein (APP) by physically interacting with the APP secretases. CD9, CD63, CD81, Tspan12, Tspan15 are among the tetraspanins involved in the intracellular transport and in the stabilization of the gamma secretase complex or ADAM10 as the major APP alpha secretase. They also directly regulate, most likely in concert with other tetraspanins, the proteolytic function of these membrane embedded enzymes. Despite the knowledge about the interaction of tetraspanins with the secretases not much is known about their physiological role, their importance in Alzheimer's Disease and their exact mode of action. This review aims to summarize the current knowledge and open questions regarding the biology of tetraspanins and the understanding how these proteins interact with APP processing pathways. Ultimately, it will be of interest if tetraspanins are suitable targets for future therapeutical approaches.

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“…Generation of destination vectors with RFP-A and RFP-B located 3′ of the Gateway recombination site has been previously described [ 42 ]. HEK293T cells were seeded at a density of 2.5 × 10 4 cells/mL in μ-dishes (Ibidi, Gräfelfing, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…HT29 cells were lysed in TNE (25 mM Tris, 150 mM NaCl, 5 mM EDTA, protease inhibitors) containing either 1% Triton X-100 or 1% Brij-98. Sucrose gradient preparation, centrifugation and analysis of the corresponding fractions were performed as described previously [ 42 , 43 ].…”

Section: Methodsmentioning

confidence: 99%

Tetraspanin 8 Subfamily Members Regulate Substrate-Specificity of a Disintegrin and Metalloprotease 17

Müller

Saunders

Senftleben

et al. 2022

Cells

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Ectodomain shedding is an irreversible process to regulate inter- and intracellular signaling. Members of the a disintegrin and metalloprotease (ADAM) family are major mediators of ectodomain shedding. ADAM17 is involved in the processing of multiple substrates including tumor necrosis factor (TNF) α and EGF receptor ligands. Substrates of ADAM17 are selectively processed depending on stimulus and cellular context. However, it still remains largely elusive how substrate selectivity of ADAM17 is regulated. Tetraspanins (Tspan) are multi-membrane-passing proteins that are involved in the organization of plasma membrane micro-domains and diverse biological processes. Closely related members of the Tspan8 subfamily, including CD9, CD81 and Tspan8, are associated with cancer and metastasis. Here, we show that Tspan8 subfamily members use different strategies to regulate ADAM17 substrate selectivity. We demonstrate that in particular Tspan8 associates with both ADAM17 and TNF α and promotes ADAM17-mediated TNF α release through recruitment of ADAM17 into Tspan-enriched micro-domains. Yet, processing of other ADAM17 substrates is not altered by Tspan8. We, therefore, propose that Tspan8 contributes to tumorigenesis through enhanced ADAM17-mediated TNF α release and a resulting increase in tissue inflammation.

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Tetraspanin 8 is an interactor of the metalloprotease meprin β within tetraspanin-enriched microdomains

Cited by 13 publications

References 40 publications

The Metalloprotease Meprin β Is an Alternative β-Secretase of APP

The Metalloprotease Meprin β Is an Alternative β-Secretase of APP

The Emerging Role of Tetraspanins in the Proteolytic Processing of the Amyloid Precursor Protein

Tetraspanin 8 Subfamily Members Regulate Substrate-Specificity of a Disintegrin and Metalloprotease 17

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