Siglecs in Brain Function and Neurological Disorders
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cells Review Siglecs in Brain Function and Neurological Disorders Shoib Sarwar Siddiqui *, Rachel Matar, Maxime Merheb, Rawad Hodeify, Cijo George Vazhappilly, John Marton, Syed Azharuddin Shamsuddin and Hussain Al Zouabi Department of Biotechnology, American University of Ras Al Khaimah (AURAK), Ras Al Khaimah 10021, UAE; [email protected] (R.M.); [email protected] (M.M.); [email protected] (R.H.); [email protected] (C.G.V.); [email protected] (J.M.); [email protected] (S.A.S.); [email protected] (H.A.Z.) * Correspondence: [email protected]; Tel.: +971-50-915-0462 Received: 14 August 2019; Accepted: 20 September 2019; Published: 22 September 2019 Abstract: Siglecs (Sialic acid-binding immunoglobulin-type lectins) are a I-type lectin that typically binds sialic acid. Siglecs are predominantly expressed in immune cells and generate activating or inhibitory signals. They are also shown to be expressed on the surface of cells in the nervous system and have been shown to play central roles in neuroinflammation. There has been a plethora of reviews outlining the studies pertaining to Siglecs in immune cells. However, this review aims to compile the articles on the role of Siglecs in brain function and neurological disorders. In humans, the most abundant Siglecs are CD33 (Siglec-3), Siglec-4 (myelin-associated glycoprotein/MAG), and Siglec-11, Whereas in mice the most abundant are Siglec-1 (sialoadhesin), Siglec-2 (CD22), Siglec-E, Siglec-F, and Siglec-H. This review is divided into three parts. Firstly, we discuss the general biological aspects of Siglecs that are expressed in nervous tissue. Secondly, we discuss about the role of Siglecs in brain function and molecular mechanism for their function. Finally, we collate the available information on Siglecs and neurological disorders. It is intriguing to study this family of proteins in neurological disorders because they carry immunoinhibitory and immunoactivating motifs that can be vital in neuroinflammation. Keywords: Siglecs; sialic acid; ganglioside; brain; neurological disorder; myelin; multiple sclerosis; Alzheimer’s disease; microglia; ITIM; ITAM 1. Introduction Glycosylation is vital for normal brain function and an alteration in this process may lead to nervous disorders and death [1,2]. Glycosylated proteins, carbohydrate moieties, and lectins have been studied in brain function and neurological disorders [1,2]. One of the types of glycosylation that is abundantly found in the brain is sialylation. Sialic acid is a nine-carbon monosaccharide that is present at the terminal end of glycoproteins and glycolipids in higher invertebrates and all vertebrates [3]. Sialic acids (Sia) are also called “neuraminic acids” and this nomenclature is based on their discovery. In 1936, Gunnar Blix isolated them from saliva and named them Sialic acids (the Greek word for Saliva). In 1941 Ernst Klenk isolated them from brain glycolipids and named them neuraminic acid for the neurons in brain [3]. The role of sialic acid in brain development and function is compiled in an excellent review by Schnaar et al. [4]. Siglecs, which are cell surface receptors that bind sialic acids, are abundantly found in the immune cells [5]. The Siglec Family The discovery of Siglecs dates back to 1990 when CD22 (Siglec-2), B cell specific protein’s cDNA was cloned, and it was observed that this protein carries many immunoglobulin-like domains [6]. One Cells 2019, 8, 1125; doi:10.3390/cells8101125 www.mdpi.com/journal/cells Cells 2019, 8, 1125 2 of 15 Cells 2019, 8, x 2 of 16 year later, it was found that CD22 binds with sialylated glycoproteins thus revealing its role as sialic acid bindingOne year lectin later, [7 ].it Anotherwas found Siglec, that CD22 mouse binds macrophage with sialylated specific glycoproteins receptor/sheep thus erythrocyte revealing receptorits role as sialic acid binding lectin [7]. Another Siglec, mouse macrophage specific receptor/sheep erythrocyte (original name- sialoadhesin/Siglec-1) was purified and characterized from mouse spleen. It was found receptor (original name- sialoadhesin/Siglec-1) was purified and characterized from mouse spleen. It that it can agglutinate sheep and human erythrocytes in sialic acid-dependent manner [8]. Subsequent was found that it can agglutinate sheep and human erythrocytes in sialic acid-dependent manner [8]. studies were carried out that identified and characterized Sialoadhesin, CD22, and myelin-associated Subsequent studies were carried out that identified and characterized Sialoadhesin, CD22, and glycoprotein (MAG/Siglec-4) as immunoglobulin-like domains containing the sialoadhesin family [9,10]. myelin-associated glycoprotein (MAG/Siglec-4) as immunoglobulin-like domains containing the Finallysialoadhesin in 1998, Paul family Crocker [9,10]. and Finally Ajit Varki in 1998, with Paul others, Crocker named and thisAjit familyVarki with of proteins others, named “Siglecs” this which family standsof for proteins sialic acid “Siglecs” binding which immunoglobulin-type stands for sialic acid lectinsbinding [11 immunoglobulin-type]. lectins [11]. SiglecsSiglecs are type are Itype transmembrane I transmembrane receptors receptors that that bind bind sialic sialic acids. acids. Siglecs Siglecs are are predominantly predominantly expressedexpressed on the on surface the surface of immune of immune cells cells [12]. [12]. The Th humane human and and mouse mouse Siglecs Siglecs are are shown shown in in Figures Figure1 1 and2.and The Figure human 2. SiglecsThe human family Siglecs contains family 15 contains members 15 members (Figure1) (Figure that are 1) basicallythat are basically classified classified into two groups:into two Evolutionary groups: Evolutionary conserved cons Siglecserved and Siglecs rapidly and rapidly evolving evolving Siglecs. Siglecs. As the As name the name suggests, suggests, the evolutionarythe evolutionary conserved conserved ones have ones the true have orthologues the true orthologues present in mammalianpresent in mammalian species. The species. members The of conservedmembers Siglecs of conserved are Siglec-1, Siglecs CD22, are MAG,Siglec-1, and CD22, Siglec-15 MAG, (Figure and Siglec-151). The rapidly-evolving(Figure 1). The rapidly- ones do notevolving exist as trueones orthologuesdo not exist as in true the mammalianorthologues in species the mammalian and more species commonly and more called commonly CD33-related called Siglecs.CD33-related In primates, Siglecs. the members In primat of thees, CD33-related the members Siglecs of the areCD33-relat CD33 (Siglec-3),ed Siglecs Siglec-5-14, are CD33 Siglec-16,(Siglec-3), and Siglec-17Siglec-5-14, (Figure Siglec-16,1)[ 5, 12and,13 Siglec-17]. In mice, (Figure the Siglecs 1) [5,12,13]. family In mice, contains the Siglecs 8 members family (Figure contains2). 8 Siglec-1, members Siglec-2,(Figure and 2). MAG Siglec-1, have Siglec-2, true homologs and MAG in have humans true ho andmologs mice. in Siglecshumans are and a mice. rapidly Siglecs evolving are a rapidly gene family.evolving Due to thisgene reason, family. many Due to Siglecs this reason, do not many have trueSiglecs homologs do not have present true between homologs humans present and between mice. Basedhumans on the expression and mice. patternBased on and the function expression there pattern is annotation and function of some there mouse is annotation and human of some Siglecs mouse as functionallyand human equivalent Siglecs paralogs.as functionally Siglec-9 equivalent is functionally paralogs. equivalent Siglec-9 is functionally to Siglec-E equivalent whereas Siglec-8 to Siglec-E is whereas Siglec-8 is functionally equivalent to Siglec-F [5,12,13]. The mouse and human CD33 are functionally equivalent to Siglec-F [5,12,13]. The mouse and human CD33 are completely different. completely different. They have different intracellular domains, different expression patterns, and They have different intracellular domains, different expression patterns, and bind to different ligands. bind to different ligands. Therefore, the studies that are carried out on mouse CD33 can usually not Therefore, the studies that are carried out on mouse CD33 can usually not be extrapolated to human be extrapolated to human CD33 and vice versa [14]. CD33 and vice versa [14]. Siglec-1/Sialoadhesin Human Siglec Family V-Set Domain V-Set Domain with Arg mutation C2-Set Domain K Lysine residue R Arginine residue ITIM motif ITIM-like motif Siglec-2/CD22 Transmembrane Domain Siglec-4/MAG Siglec-10 Siglec-XII Siglec-5 Siglec-11 Siglec-16 Siglec-3/CD33 Siglec-6 Siglec-7 Siglec-8 Siglec-9 Siglec-14 Siglec-15 K K R FigureFigure 1. The human1. The human Siglec family Siglec receptors.family receptors. The human The Siglechuman receptors Siglec receptors are expressed are expressed on the immune on the cells andimmune have cells Ig-like and extracellular have Ig-like domain.extracellular They domain carry. They one extracellularcarry one extrace V-setllular domain V-set thatdomain binds that with sialicbinds acid with ligands. sialic acid Beneath ligands. V-setBeneath domain V-set thesedomain receptors these receptor carrys dicarryfferent different numbers numbers of C2-set of C2- domains.set domains. Siglec-3 andSiglec-3 Siglec-15 and Siglec-15 have only have one only C2-set one C2 domain-set domain while while Siglec-1 Siglec-1 has has 16 16 C2-set C2-set domains. domains. As anAs exception, an exception, Siglec-XII Siglec-XII has has two two V-set V-set domains domains but but both both of of themthem do not not have have critical critical arginine arginine and and doesdoes not not bind bind with with sialic sialic acid acid ligand. ligand. Most Most of of the the Siglecs Siglecs have have ITIM ITIM and and ITIM-like ITIM-like domain domain that that facilitatesfacilitates inhibitory inhibitory signal signal to the to cells. the cells. Siglec-14, Siglec-14, -15, -15, and and -16 have-16 have positively positively charged charged residue residue in in the the transmembrane domain that recruit Dap12 and facilitate activating signal to the cells.