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The Emerging Role of the Mammalian Glycocalyx in Functional Membrane Organization and Immune System Regulation

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The Emerging Role of the Mammalian Glycocalyx in Functional Membrane Organization and Immune System Regulation fcell-08-00253 April 9, 2020 Time: 18:25 # 1 REVIEW published: 15 April 2020 doi: 10.3389/fcell.2020.00253 The Emerging Role of the Mammalian Glycocalyx in Functional Membrane Organization and Immune System Regulation Leonhard Möckl* Department of Chemistry, Stanford University, Stanford, CA, United States All cells in the human body are covered by a dense layer of sugars and the proteins and lipids to which they are attached, collectively termed the “glycocalyx.” For decades, the organization of the glycocalyx and its interplay with the cellular state have remained enigmatic. This changed in recent years. Latest research has shown that the glycocalyx is an organelle of vital significance, actively involved in and functionally relevant for various cellular processes, that can be directly targeted in therapeutic contexts. This review gives a brief introduction into glycocalyx biology and describes the specific Edited by: challenges glycocalyx research faces. Then, the traditional view of the role of the Falk Nimmerjahn, glycocalyx is discussed before several recent breakthroughs in glycocalyx research are University of Erlangen Nuremberg, Germany surveyed. These results exemplify a currently unfolding bigger picture about the role of Reviewed by: the glycocalyx as a fundamental cellular agent. Vincenzo Desiderio, Second University of Naples, Italy Keywords: glycocalyx, membrane organization, cancer, immune system, cancer immune therapy, Zhong Yao, immunosynapse, siglecs, KRAS University of Toronto, Canada *Correspondence: Leonhard Möckl INTRODUCTION [email protected] Every cell in the human body – endothelial cells, immune cells, muscle cells, blood cells, neurons, Specialty section: and all the others – exhibit a glycocalyx. “Glycocalyx” literarily translates to “sweet husk.” “Sweet” This article was submitted to indicates its key building units – various sugars (or monosaccharides) like glucose, mannose, Cellular Biochemistry, galactose, and many others. “Husk” points toward the location of these sugars – they reside a section of the journal extracellularly on the cell membrane, surrounding the cell like a cloak. The sugars in the glycocalyx Frontiers in Cell and Developmental are connected with each other in a plethora of ways, forming sugar conjugates or “glycans.” Their Biology sizes range from few to tens of thousands of monosaccharide units. Glycans are either free or linked Received: 24 January 2020 to proteins, which creates glycoproteins and proteoglycans, or lipids, which creates glycolipids. Accepted: 25 March 2020 The term “glycocalyx” is thus an umbrella term for the entirety of free glycans, glycoproteins, Published: 15 April 2020 proteoglycans, and glycolipids present on the cell surface (Figure 1). Citation: The glycocalyx has been connected to a variety of fundamental cellular and organismic events Möckl L (2020) The Emerging such as blastocyst implantation, embryonic development, leukocyte adhesion, or viral and bacterial Role of the Mammalian Glycocalyx in Functional Membrane Organization infections (Matrosovich et al., 2004; Lipowsky, 2012; Weber et al., 2014; Constantinou et al., and Immune System Regulation. 2015; Stanley and Cummings, 2015; Formosa-Dague et al., 2018). Given the omnipresence of the Front. Cell Dev. Biol. 8:253. glycocalyx in the human body and the importance of the processes it has been connected to, doi: 10.3389/fcell.2020.00253 one might assume that its functional role has been investigated and understood in detail. This Frontiers in Cell and Developmental Biology| www.frontiersin.org 1 April 2020| Volume 8| Article 253 fcell-08-00253 April 9, 2020 Time: 18:25 # 2 Möckl The Emerging Role of the Glycocalyx FUNDAMENTALS OF GLYCOCALYX BIOLOGY From Monosaccharides to Glycopolymers The key component of the glycocalyx are sugars or monosaccharides. They are also referred to as carbohydrates as they were initially identified as hydrates of carbon, Cx(H2O)y. However, this name does not capture the true chemistry of sugars well. Rather, sugars can be considered polyhydroxylated carbonyl compounds. For example, glucose is an aldo-hexose, i.e., a six-membered chain of carbon atoms, where the first carbon exhibits a carbonyl group and the other five groups each carry a hydroxyl group. Fructose is a keto-hexose: Here, the second carbon atom in the chain carries the carbonyl group. Thus, the positioning of the carbonyl group and the orientation FIGURE 1 | Schematic depiction of the glycocalyx. The glycocalyx is a central of the hydroxyl group at the chiral carbon atoms determines the constituent of any cell, consisting of sugars and the proteins and lipids to monosaccharide structure. For example, glucose, galactose, and which they are attached. For simplicity, the different sugars found within the mannose are all aldo-hexoses, which differ only in the orientation glycocalyx are depicted with the same symbol (blue hexagons). Note that the of one hydroxyl group (Figure 2A, top row), emphasizing the depiction is roughly to scale, i.e., membrane proteins are buried under sugars. importance of stereochemistry in glycobiology. In solution, monosaccharides exist as a mixture between an open, chain-like form and a cyclic form. The latter is formed is, however, not the case. In contrast, the glycocalyx has been by an intramolecular ring closure reaction where a hydroxyl surprisingly elusive. For many decades, it was assumed that the group reacts with the carbon atom carrying the carbonyl group, glycocalyx merely forms a protective layer on the cell surface typically forming five- or six-membered rings with four or with no regulative potential. In retrospect, this might seem a bit five carbon atoms and one oxygen atom. The ratio of open surprising: The glycocalyx resides directly at the periphery of the and closed form depends on the structure of the sugar, but cell and forms the interface of the cell with the extracellular space. the closed form is usually energetically more stable and thus Thus, it seems reasonable to assume that it is involved in the many prevalent. The carbon derived from the carbonyl group is processes that are related to the cell membrane. called “anomeric carbon.” Dependent on the orientation of the However, there is a simple reason for the remarkable hydroxyl group at the anomeric carbon, the monosaccharide elusiveness of the glycocalyx: The glycocalyx confronts any exists either in the a- or b-anomer. Via ring opening and researcher with an incredible complexity at all levels, from reclosing, the two anomers can interchange. For a detailed synthesis all the way to structural organization (see sections overview of the intriguing chemistry of sugars, see the literature “From Monosaccharides to Glycopolymers” and “Biosynthesis of (Lindhorst, 2007). Glycocalyx Components”). Because of this, traditional methods Figure 2A depicts the most common sugars found in the to study biological systems are of very limited use when applied human body and their pictorial representations according to the to the glycocalyx (see section “Problems Specific to Glycocalyx symbol nomenclature for glycans (SNFG) (Varki et al., 2015; Research and Approaches to Solve Them”). Therefore, for a Neelamegham et al., 2019). As mentioned above, stereochemistry long time, the picture of the glycocalyx was very incomplete as plays a central role in glycobiology. The second aspect that tools for its detailed investigation were not available. Specifically, determines monosaccharide identity are chemical modifications the prominent size of the glycocalyx – typically several 10 s to such as oxidation of hydroxyl groups, N-acetylation, sulfation, few 100 s of nanometers and thus typically burying even large and many more. The resulting complexity already at the level of membrane proteins – was underestimated for a long time. individual monosaccharides is remarkable. This situation dramatically changed in recent years. Novel The complexity of monosaccharides is, however, just a small tools to image, model, characterize, and manipulate the hint at the complexity of oligo- and polysaccharides, i.e., glycocalyx precisely have brought it into the spotlight of glycoconjugates of several to many monosaccharide units. For biochemical and medical research. Rather than a passive coat, the example, let’s consider the formation of a disaccharide that glycocalyx is an active player in cell biology, chiefly involved in a consist of two glucose units. The glyosidic bond is formed range of vital cellular processes. by the anomeric carbon of the first glucose unit and any In this review, I will first give a brief, general introduction hydroxyl group of the other glucose unit. As each of the to fundamental concepts in glycocalyx biology. Then, I will two units can exist in the a- or b-anomer, there are already discuss some roles that were traditionally assigned to the 19 disaccharides consisting of two glycose units. Moving to glycocalyx before presenting breakthrough discoveries that have slightly larger hexasaccharides that may include all the sugars revolutionized this traditional view in recent years. found in the human body, the number of possible isomers Frontiers in Cell and Developmental Biology| www.frontiersin.org 2 April 2020| Volume 8| Article 253 fcell-08-00253 April 9, 2020 Time: 18:25 # 3 Möckl The Emerging Role of the Glycocalyx FIGURE 2 | Important sugars found in humans and examples of sugar conjugates found in the glycocalyx. (A) Common sugars found in humans and their pictorial representation according to the symbol nomenclature
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