Tetraspanins in the Regulation of Mast Cell Function

Medical Microbiology and Immunology (2020) 209:531–543 https://doi.org/10.1007/s00430-020-00679-x REVIEW Tetraspanins in the regulation of mast cell function Zane Orinska1 · Philipp M. Hagemann1 · Ivana Halova2 · Petr Draber2 Received: 17 February 2020 / Accepted: 6 May 2020 / Published online: 7 June 2020 © The Author(s) 2020 Abstract Mast cells (MCs) are long-living immune cells highly specialized in the storage and release of diferent biologically active compounds and are involved in the regulation of innate and adaptive immunity. MC degranulation and replacement of MC granules are accompanied by active membrane remodelling. Tetraspanins represent an evolutionary conserved family of transmembrane proteins. By interacting with lipids and other membrane and intracellular proteins, they are involved in organisation of membrane protein complexes and act as “molecular facilitators” connecting extracellular and cytoplasmic signaling elements. MCs express diferent tetraspanins and MC degranulation is accompanied by changes in membrane organisation. Therefore, tetraspanins are very likely involved in the regulation of MC exocytosis and membrane reorganisation after degranulation. Antiviral response and production of exosomes are further aspects of MC function characterized by dynamic changes of membrane organization. In this review, we pay a particular attention to tetraspanin gene expression in diferent human and murine MC populations, discuss tetraspanin involvement in regulation of key MC signaling complexes, and analyze the potential contribution of tetraspanins to MC antiviral response and exosome production. In-depth knowledge of tetraspanin-mediated molecular mechanisms involved in diferent aspects of the regulation of MC response will be benefcial for patients with allergies, characterized by overwhelming MC reactions. Keywords Tetraspanins · Mast cells · FcεRI · Mast cell degranulation · Allergy · Antiviral immune response · Exosomes Introduction bronchoconstriction) or generalized systemic reactions (e.g., changes in blood pressure during anaphylactic shock) Mast cells (MCs) are long-living cells highly specialized are the consequences of MC response. Mainly associated in the storage and release of diferent biologically active with diferent pathological conditions such as allergies or compounds. Located in diferent tissues and organs in the asthma, MCs are able to recognize pathogens and regulate proximity of blood vessels and nerves, MCs quickly respond local and systemic infammation in the context of protective to changes in the environment by granule exocytosis and immune reaction [1–4]. As cells sensing the environment release of mediators. Organ-restricted local reactions rel- on one hand and changes in organism homeostasis on the evant for the specifc function (e.g., local extravasation, other one, MCs display heterogeneity in granule composi- tion and organization of membrane complexes [5, 6]. Dif- Edited by Charlotte M. de Winde. ferent developmental origin [7, 8] and maturation under the infuence of tissue-specifc microenvironment are at least This article is part of the Special Issue on Tetraspanins in Infection two factors responsible for MC heterogeneity and tissue- and Immunity. specifc MC features. MC degranulation starts by receptor- * Zane Orinska mediated incoming signals followed by reorganisation of [email protected] granules and actin cytoskeleton [9]. These processes end up in granule movement to the cell surface, granule membrane 1 Division of Experimental Pneumology, Research Center fusion with plasma membrane, and granule content release. Borstel, Leibniz Lungenzentrum, Airway Research Center North, German Center for Lung Research (DZL), Borstel, IgE-dependent MC degranulation is an interplay between the Germany high afnity IgE Fc receptor (FcεRI) complex, activator and 2 Department of Signal Transduction, Institute of Molecular inhibitory proteins, membrane lipids, downstream tyrosine Genetics of the Czech Academy of Sciences, Prague, kinases, cytoskeletal proteins, as well as proteins and lipids Czech Republic Vol.:(0123456789)1 3 532 Medical Microbiology and Immunology (2020) 209:531–543 involved in granule membrane organization [10–12]. Behind are produced by en bloc duplications [25]. Therefore, it is IgE-antigen binding, MC degranulation could be induced possible that tetraspanins can compensate the absence of by proteases (e.g., thrombin), danger signals (e.g., ATP), each other, leading to mild phenotypes of single tetraspanin toxins, small polycationic compounds, and neuropeptides knockout mice. [13, 14]. Tetraspanins—an evolutionary conserved family Palmitoylation is the post-translational modification of transmembrane proteins—are involved in organisation of where palmitoyl-CoA is enzymatically bound to a thiol membrane protein complexes. Therefore, tetraspanins prob- group of a cysteine [26]. For tetraspanins, this seems to take ably play an important role in the regulation of MC function, place mainly in the Golgi complex, but modifcations at the particularly, in regulation of exocytosis and membrane reor- plasma membrane are also very likely [27]. A recent study ganisation during the degranulation and after degranulation from Rodenburg et al. shows that palmitoylation is a stochas- is completed. tic process rather than being defned by distinct motifs [28]. All tetraspanin proteins can be palmitoylated. Tetraspanins with mutated palmitoylation sites show decreased associa- Introduction to the tetraspanin family tion with their interaction partners including cholesterol [18, of proteins 29]. Ubiquitination is a process by which ubiquitin is enzy- Tetraspanins are membrane glycoproteins consisting of matically coupled to free lysine residues on proteins. Besides 204–393 amino acids with four conserved transmembrane signaling, poly-ubiquitination leads to protein degradation helices, a small extracellular loop EC1 (9–26 amino acids in the proteasome. The Single Subunit Transmembrane E3 long), and a large extracellular loop EC2 (up to 138 amino Ligase Gene Related to Anergy in Lymphocytes (GRAIL) acids long) [15–17]. The EC2, being responsible for binding can ubiquitinate tetraspanins, specifcally at the N-terminus partner proteins, contains a conserved Cys–Cys–Gly amino by binding the EC2 of the tetraspanin [30]. Ubiquitination of acid motif (CCG-motif), two other conserved cysteines, and Tspan6 is critical for interaction with mitochondrial antiviral up to four additional cysteines [18]. The intracellular N- signaling (MAVS) and recruitment of downstream signaling and C-termini are usually short. Characteristic post-trans- proteins [31]. lational modifcations of tetraspanins are N-glycosylation Glycosylation of tetraspanins at asparagines in the EC2 (at asparagines) at the EC2, palmitoylation (at cysteines), is common. Loss of glycosylation leads to multiple efects, and ubiquitination (at lysines) [18]. Cholesterol binding is a e.g., loss of glycosylation in CD151 afects glycosylation of general feature of tetraspanins, since 30 out of 33 human tet- the binding partner of CD151, integrin α3β1 [32]. Likewise, raspanins contain at least one cholesterol-binding motif [19]. in B cells, CD81 is required for CD19 surface expression Interaction between tetraspanins and cholesterol is necessary and proper glycosylation of CD19 depends on CD81 in the and sufcient in the formation of migrasomes—migration- Golgi complex [33]. dependent membrane-bound cellular organelles [20]. Cho- Recently, it was found that the tetraspanin CD37 them- lesterol binding was verifed after solving the structure of selves can take part in signal transduction and could be CD81 [21]. The crystal structure of CD81 also indicates phosphorylated at the N- and C-termini [34]. Whether this that EC2 exists in an open and a closed conformation [21]. observation is human CD37-specifc or B-cell chronic leuke- Tetraspanins were thought to be mixed together in tetraspa- mia cell-restricted, does phosphorylation take place in other nin-enriched microdomains, but super-resolution data indi- tetraspanins bearing identical or similar ITIM-like motifs cate TEMs consisting only of one type of tetraspanin [22]. and whether phosphorylation afects interaction with other Whether tetraspanin distribution in membranes, particularly membrane proteins, should be further investigated. in immune cells, is cell-type specifc is unknown. It is also Altogether, tetraspanins as an evolutionary old mem- unclear whether tetraspanin distribution difers between nor- brane protein family are involved in a variety of diferent mal and malignant cells. Such efects have been described, cellular processes such as cell development, motility, fusion, e.g., for organisation of B-cell receptor complex [23]. and cancer development [18]. Direct association of target In humans, 33 tetraspanins have been identifed so far. proteins with several tetraspanin partners suggests that the The nomenclature of genes and proteins of the tetraspanin function of the target protein could be dependent on associ- family could be found at the HUGO Gene Nomenclature ated tetraspanins [35]. Interacting with other membrane pro- web page (www.genen ames.org). According to phyloge- teins, e.g., integrins, G protein-coupled receptors (GPCRs), netic analysis, the tetraspanin family members can be sub- a disintegrin and metalloproteases (ADAMs), tetraspanins divided into four groups: the CD family, the CD63 family, are organizing membranes in functional microdomains [36] the uroplakin

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