TspanC8 tetraspanins differentially regulate ADAM10 endocytosis and half-life

Eschenbrenner, Etienne; Jouannet, Stéphanie; Clay, Denis; Chaker, Joëlle; Boucheix, Claude; Brou, Christel; Tomlinson, Michael G.; Charrin, Stéphanie; Rubinstein, Eric

doi:10.26508/lsa.201900444

Cited by 29 publications

(40 citation statements)

References 47 publications

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“…In that study, an approximate 70% siRNA knockdown of ADAM10 in the HCT116 and U2OS cell lines reduced Tspan5 expression by 40%, and ADAM10 was shown to be important for trafficking of Tspan5 out of the ER (15). Our findings are also consistent with a very recent study showing that Tspan15 surface expression is reduced by 60% in ADAM10-knockout PC3 prostate cancer cells (29). In the current study, we investigated Tspan15 expression in the absence of ADAM10 by CRISPR/Cas9 knockout in three different cell lines, namely A549, HEK-293T and Jurkat.…”

Section: Discussionsupporting

confidence: 92%

The tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor complex

Koo

Harrison

Noy

et al. 2020

Journal of Biological Chemistry

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A disintegrin and metalloprotease 10 (ADAM10) is a transmembrane protein essential for embryonic development, and its dysregulation underlies disorders such as cancer, Alzheimer’s disease and inflammation. ADAM10 is a “molecular scissor” that proteolytically cleaves the extracellular region from >100 substrates, including Notch, amyloid precursor protein, cadherins, growth factors, and chemokines. ADAM10 has been recently proposed to function as six distinct scissors with different substrates, depending on its association with one of six regulatory tetraspanins, termed TspanC8s. However, it remains unclear to what degree ADAM10 function critically depends on a TspanC8 partner, and a lack of monoclonal antibodies specific for most TspanC8s has hindered investigating this question. To address this knowledge gap, here we designed an immunogen to generate the first monoclonal antibodies targeting Tspan15, a model TspanC8. The immunogen was created in an ADAM10-knockout mouse cell line stably overexpressing human Tspan15, because we hypothesized that expression in this cell line would expose epitopes that are normally blocked by ADAM10. Following immunization of mice, this immunogen strategy generated four Tspan15 antibodies. Using these antibodies, we show that endogenous Tspan15 and ADAM10 co-localize on the cell surface, that ADAM10 is the principal Tspan15-interacting protein, that endogenous Tspan15 expression requires ADAM10 in cell lines and primary cells, and that a synthetic ADAM10/Tspan15 fusion protein is a functional scissor. Furthermore, two of the four antibodies impaired ADAM10/Tspan15 activity. These findings suggest that Tspan15 directly interacts with ADAM10 in a functional scissor complex.

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Section: Discussionsupporting

confidence: 92%

The tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor complex

Koo

Harrison

Noy

et al. 2020

Journal of Biological Chemistry

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“…3b). This finding confirms previous reports that ADAM10 undergoes constitutive internalization [13,36] and also indicates that GI promotes internalization of ADAM10.…”

Section: Gi-induced Adam10 Downregulation Coincides With Adam10 Releasupporting

confidence: 92%

The metalloproteinase ADAM10 requires its activity to sustain surface expression

Seifert¹,

Düsterhöft²,

Wozniak³

et al. 2020

Cell. Mol. Life Sci.

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The metalloproteinase ADAM10 critically contributes to development, inflammation, and cancer and can be controlled by endogenous or synthetic inhibitors. Here, we demonstrate for the first time that loss of proteolytic activity of ADAM10 by either inhibition or loss of function mutations induces removal of the protease from the cell surface and the whole cell. This process is temperature dependent, restricted to mature ADAM10, and associated with an increased internalization, lysosomal degradation, and release of mature ADAM10 in extracellular vesicles. Recovery from this depletion requires de novo synthesis. Functionally, this is reflected by loss and recovery of ADAM10 substrate shedding. Finally, ADAM10 inhibition in mice reduces systemic ADAM10 levels in different tissues. Thus, ADAM10 activity is critically required for its surface expression in vitro and in vivo. These findings are crucial for development of therapeutic ADAM10 inhibition strategies and may showcase a novel, physiologically relevant mechanism of protease removal due to activity loss.

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“…Interestingly, anti‐tetraspanin antibodies and LEL proteins reduce S. aureus adhesion to host cells, and more recently, it was found that the short peptides derived from the LEL domain of CD9 could reduce S. aureus adhesion to epithelial cell lines, primary keratinocytes and 3D tissue engineered model of the human skin (Figure 2F) (Green et al, 2011; Ventress et al, 2016). Apart from host cell invasion, Tspan C8 contributes to the spread of S. aureus by promoting the trafficking of ADAM10 from the endoplasmic reticulum to host cell surface (Eschenbrenner et al, 2020). In fact, S. aureus secretes an α‐toxin that interacts with and activates the metalloprotease ADAM10, which has been shown to be a receptor for bacteria α‐toxin (Figure 2J) (Virreira Winter, Zychlinsky, & Bardoel, 2016).…”

Section: Tetraspanin‐dependent Invasion and Colonisation Of Host Cellmentioning

confidence: 99%

The roles of tetraspanins in bacterial infections

Karam

Méresse

Kremer

et al. 2020

Cellular Microbiology

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Tetraspanins, a wide family composed of 33 transmembrane proteins, are associated with different types of proteins through which they arbitrate important cellular processes such as fusion, adhesion, invasion, tissue differentiation and immunological responses. Tetraspanins share a comparable structural design, which consists of four hydrophobic transmembrane domains with cytoplasmic and extracellular loops. They cooperate with different proteins, including other tetraspanins, receptors or signalling proteins to compose functional complexes at the cell surface, designated tetraspanin‐enriched microdomains (TEM). Increasing evidences establish that tetraspanins are exploited by numerous intracellular pathogens as a doorway for entering and replicating within human cells. Although previous surveys focused mainly on viruses and parasites, it is now becoming clear that bacteria interact with tetraspanins, using TEM as a “gateway” to infection. In this review, we examine the biological functions of tetraspanins that are relevant to bacterial infective procedures and consider the available data that reveal how different bacteria benefit from host cell tetraspanins in infection and in the pathogenesis of diseases. We will also emphasise the stimulating potentials of targeting tetraspanins for preventing bacterial infectious diseases, using specific neutralising antibodies or anti‐adhesion peptide‐based therapies. Such innovative therapeutic opportunities may deliver alternatives for fighting difficult‐to‐manage and drug‐resistant bacterial pathogens.

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TspanC8 tetraspanins differentially regulate ADAM10 endocytosis and half-life

Abstract: This study demonstrates that the tetraspanins Tspan5 and Tspan15 which directly associate with the metalloprotease ADAM10 have an opposite impact on its endocytosis and half-life.

Cited by 29 publications

References 47 publications

The tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor complex

The tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor complex

The metalloproteinase ADAM10 requires its activity to sustain surface expression

The roles of tetraspanins in bacterial infections

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