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Regulation of Leukocytes by Tspanc8 Tetraspanins And View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of Birmingham Research Portal University of Birmingham Regulation of Leukocytes by TspanC8 Tetraspanins and the “Molecular Scissor” ADAM10 Matthews, Alexandra; Koo, Chek Ziu; Szyroka, Justyna; Harrison, Neale; Kanhere, Aditi; Tomlinson, Michael DOI: 10.3389/fimmu.2018.01451 License: Creative Commons: Attribution (CC BY) Document Version Publisher's PDF, also known as Version of record Citation for published version (Harvard): Matthews, A, Koo, CZ, Szyroka, J, Harrison, N, Kanhere, A & Tomlinson, M 2018, 'Regulation of Leukocytes by TspanC8 Tetraspanins and the “Molecular Scissor” ADAM10', Frontiers in immunology, vol. 9, 1451. https://doi.org/10.3389/fimmu.2018.01451 Link to publication on Research at Birmingham portal Publisher Rights Statement: Matthews AL, Koo CZ, Szyroka J, Harrison N, Kanhere A and Tomlinson MG (2018) Regulation of Leukocytes by TspanC8 Tetraspanins and the “Molecular Scissor” ADAM10. Front. Immunol. 9:1451. doi: 10.3389/fimmu.2018.01451. First published by Frontiers Media. Checked 30/7/18. General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposes permitted by law. •Users may freely distribute the URL that is used to identify this publication. •Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of private study or non-commercial research. •User may use extracts from the document in line with the concept of ‘fair dealing’ under the Copyright, Designs and Patents Act 1988 (?) •Users may not further distribute the material nor use it for the purposes of commercial gain. Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document. When citing, please reference the published version. Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive. If you believe that this is the case for this document, please contact [email protected] providing details and we will remove access to the work immediately and investigate. Download date: 01. Mar. 2020 MINI REVIEW published: 02 July 2018 doi: 10.3389/fimmu.2018.01451 Regulation of Leukocytes by TspanC8 Tetraspanins and the “Molecular Scissor” ADAM10 Alexandra L. Matthews1, Chek Ziu Koo1,2, Justyna Szyroka1, Neale Harrison1, Aditi Kanhere1 and Michael G. Tomlinson1,2* 1 School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Birmingham, United Kingdom, 2Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham,United Kingdom A disintegrin and metalloproteinase 10 (ADAM10) is a ubiquitous transmembrane pro- tein that functions as a “molecular scissor” to cleave the extracellular regions from its transmembrane target proteins. ADAM10 is well characterized as the ligand-dependent activator of Notch proteins, which control cell fate decisions. Indeed, conditional knock- outs of ADAM10 in mice reveal impaired B-, T-, and myeloid cell development and/ or function. ADAM10 cleaves many other leukocyte-expressed substrates. On B-cells, Edited by: ADAM10 cleavage of the low-affinity IgE receptor CD23 promotes allergy and asthma, Annemiek van Spriel, Radboud University Nijmegen cleavage of ICOS ligand impairs antibody responses, and cleavage of the BAFF–APRIL Medical Centre, Netherlands receptor transmembrane activator and CAML interactor, and BAFF receptor, reduce Reviewed by: B-cell survival. On microglia, increased ADAM10 cleavage of a rare variant of the scaven- Beatrice Charreau, ger receptor triggering receptor expressed on myeloid cells 2 may increase susceptibility University of Nantes, France Peter Daniel Burrows, to Alzheimer’s disease. We and others recently showed that ADAM10 interacts with University of Alabama at Birmingham, one of six different regulatory tetraspanin membrane proteins, which we termed the United States TspanC8 subgroup, comprising Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and *Correspondence: Tspan33. The TspanC8s are required for ADAM10 exit from the endoplasmic reticulum, Michael G. Tomlinson [email protected] and emerging evidence suggests that they dictate ADAM10 subcellular localization and substrate specificity. Therefore, we propose that ADAM10 should not be regarded as a Specialty section: single scissor, but as six different scissors with distinct substrate specificities, depending This article was submitted to B Cell Biology, on the associated TspanC8. In this review, we collate recent transcriptomic data to a section of the journal present the TspanC8 repertoires of leukocytes, and we discuss the potential role of the Frontiers in Immunology six TspanC8/ADAM10 scissors in leukocyte development and function. Received: 20 April 2018 Accepted: 12 June 2018 Keywords: a disintegrin and metalloproteinase 10, tetraspanins, TspanC8s, leukocytes Published: 02 July 2018 Citation: INTRODUCTION Matthews AL, Koo CZ, Szyroka J, Harrison N, Kanhere A and The proteolytic cleavage, or “shedding,” of the extracellular region (ectodomain) of transmembrane Tomlinson MG (2018) Regulation proteins is an important mechanism for the regulation of leukocyte development and function. of Leukocytes by TspanC8 Tetraspanins and the “Molecular Shedding can initiate intracellular signal transduction via the cell-associated cleavage fragment Scissor” ADAM10. (e.g., Notch signaling to drive cell fate decisions), downregulate signaling or adhesion that requires Front. Immunol. 9:1451. cell surface receptor expression, or activate paracrine signaling through the release of growth fac- doi: 10.3389/fimmu.2018.01451 tors, cytokines, and chemokines (1). The ADAMs (a disintegrin and metalloproteinases) are one Frontiers in Immunology | www.frontiersin.org 1 July 2018 | Volume 9 | Article 1451 Matthews et al. Leukocyte Regulation by TspanC8/ADAM10 Scissors of the main proteinase families that function as sheddases and The prodomain is removed by proprotein convertases during can be regarded as “molecular scissors.” A total of 22 ADAM biosynthesis to generate a mature sheddase (5). The first crystal genes have been identified in humans, of which 12 (ADAM8, structure of the mature ADAM10 ectodomain suggests that the 9, 10, 12, 15, 17, 19, 20, 21, 28, 30, and 33) are active proteases metalloprotease exists in a closed conformation in which the with the consensus sequence (HExGHxxGxxHD) required for cysteine-rich domain partially occludes the catalytic site, but Zn2+-dependent protease activity (1). with the catalytic site in position to cleave substrates close to the plasma membrane (6). ADAM10 has at least 40 substrates, THE “MOLECULAR SCISSOR” ADAM10 including amyloid precursor protein (7), cellular prion protein (8), cadherins (9–11), and the platelet-activating collagen/fibrin One of the best-characterized ADAMs is ADAM10, due to its receptor GPVI (12, 13). ADAM10 has a number of substrates essential role in ligand-dependent cleavage of Notch proteins to that are expressed by leukocytes, or which impact on leukocyte initiate Notch signaling (2). Indeed, ADAM10-knockout mice die function, including the low-affinity IgE receptor CD23 (14, 15), at embryonic day 9.5, phenocopying double knockout mice for the endothelial cell–cell adhesion molecule vascular-endothelial two of the four Notch proteins, Notch 1 and 4 (3, 4). ADAM10 (VE)-cadherin (11), the B-cell costimulatory molecule ICOS has an N-terminal signal sequence, an inhibitory prodomain, a ligand (16), B-cell homeostasis proteins transmembrane activator metalloproteinase domain, followed by disintegrin, cysteine- and CAML interactor (TACI) (17) and BAFF receptor (BAFFR) rich, transmembrane, and cytoplasmic domains (Figure 1). (18), and triggering receptor expressed on myeloid cells 2 FIGURE 1 | Six ADAM10 scissors: Tspan14 and Tspan5 may be important for Notch activation in immune cells. (A) A schematic representation of a TspanC8 and ADAM10. (B) A model figure to show the six different TspanC8/ADAM10 complexes, which have different subcellular localizations, distinct substrate specificities, and may have different ADAM10 conformations. Notch cleavage is initiated following engagement with a Notch ligand on another cell (1), which induces a conformational change that we hypothesize allows cleavage by a Tspan14/ADAM10 or Tspan5/ADAM10 scissor (2), followed by intramembrane cleavage by γ-secretase (3), to release the intracellular domain to act as a transcription factor and drive cell fate decisions (4). Tspan10 has also been implicated in Notch activation, but its relatively low expression by immune cells suggests no substantial role in these cells. N-linked and O-linked glycosylation sites are indicated by filled ovals and short lines, respectively. Frontiers in Immunology | www.frontiersin.org 2 July 2018 | Volume 9 | Article 1451 Matthews et al. Leukocyte Regulation by TspanC8/ADAM10 Scissors (TREM2) (19, 20). ADAM10 has been implicated in myriad TspanC8-knockout mice (29, 31) and the fruit fly Drosophila (28), immune diseases including T-cell acute lymphoblastic leukemia and is reinforced by recent
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