Human Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Functions as a Dimer in Living Cells

Xie, Qiuhong; Matsunaga, Shigeru; Niimi, Setsuko; Ogawa, Setsuko; Tokuyasu, Ken; Sakakibara, Yoshikiyo; Machida, Sachiko

doi:10.1089/104454904322759920

Cited by 51 publications

(45 citation statements)

References 24 publications

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“…Our analysis of MICL, in both transduced cell lines [14] and primary cells, suggests that this molecule is highly N-glycosylated compared to its most closely related paralogs, lectin-like receptor for oxidized LDL [22], Dectin-1 [9,23], and CLEC-2 [13]. Intriguingly, the level of MICL N-glycosylation varied significantly in different leukocyte populations, which may have functional consequences for ligand binding, as shown for other receptors [24,25].…”

Section: Discussionmentioning

confidence: 64%

Human MICL (CLEC12A) is differentially glycosylated and is down‐regulated following cellular activation

Willment¹,

Pyż²,

Dennehy³

et al. 2006

Eur J Immunol

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C-type lectins are the most diverse and prevalent lectin family in immunity. Particular interest has recently been attracted by the C-type lectin-like receptors on NK cells, which appear to regulate the activation/inhibitory balance of these cells, controlling cytotoxicity and cytokine production. We previously identified a human C-type lectin-like receptor, closely related to both the beta-glucan receptor and the lectin-like receptor for oxidized-LDL, named MICL (myeloid inhibitory C-type lectin-like receptor), which we had shown using chimeric analysis to function as an inhibitory receptor. Using a novel MICL-specific monoclonal antibody, we show here that human MICL is expressed primarily on myeloid cells, including granulocytes, monocytes, macrophages, and dendritic cells. Although MICL was highly N-glycosylated in primary cells, the level of glycosylation was found to vary between cell types. MICL surface expression was down-regulated during inflammatory/activation conditions in vitro, as well as during an in vivo model of acute inflammation, which we characterize here. This suggests that human MICL may be involved in the control of myeloid cell activation during inflammation. IntroductionIn order to execute their immune (and non-immune) functions, leukocytes must interact with a broad range of endogenous and exogenous ligands and must be able to respond to these interactions appropriately. This requires a wide and flexible, yet specific and regulated, repertoire of cell surface molecules. One large family of such molecules, which are particularly important to immunity, are the C-type lectin and lectin-like receptors. C-type lectin-like receptors were first identified as dimeric molecules on NK cells. On these cells, much attention has been drawn toward their ability to regulate the balance between cellular activation and inhibition, such as cytotoxicity and cytokine production. This is achieved through signalling via intracellular ITIM present in the cytoplasmic tails of these receptors or via ITAM, of which the majority are located in the cytoplasmic tails of associated molecules, such as DAP12. The study of these activationand inhibitory NK cell receptorshas generated a number of interesting hypotheses, including immune privilege [1], the recognition of 'missing self', 'non-self' and 'induced self' [2][3][4][5], as well elucidating the underlying mechanisms of some of the immune responses to viruses [6] and malignancy [7]. Others and we have demonstrated that C-type lectinlike receptors are not restricted to NK cells, but are expressed by many other cell types including myeloid cells [8][9][10]. This introduces the novel concept that the myeloid paralogs of NK cell receptors might govern myeloid cell activation/inhibition in the same manner as those on NK cells. The genes of most C-type lectin-like molecules are located within the 'natural killer complex' (NKC), but many of those expressed by myeloid and other cells are found in a distinct cluster of genes within the NKC [10]. This cluster includes Decti...

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Section: Discussionmentioning

confidence: 64%

Human MICL (CLEC12A) is differentially glycosylated and is down‐regulated following cellular activation

Willment¹,

Pyż²,

Dennehy³

et al. 2006

Eur J Immunol

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“…Mutation of Cys140 does not affect the ox-LDLbinding activity [9,10] and does not destabilize the dimeric form of the ligand-binding domain [10]. The particular dimeric association of CTLD in human LOX-1 generates a tunnel which completely crosses the dimer with a diameter of 7.0-8.0 Å, except for a first constriction caused by the side chains of Ile149 of the two subunits and a second constriction caused by Tyr197 of subunit A, that restrict the opening to 4.0 Å [7].…”

Section: Introductionmentioning

confidence: 95%

Design of a novel LOX-1 receptor antagonist mimicking the natural substrate

Falconi

Ciccone

D’Arrigo

et al. 2013

Biochemical and Biophysical Research Communications

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a b s t r a c tThe lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the major receptor for oxidized lowdensity lipoprotein (ox-LDL) in endothelial cells, is overexpressed in atherosclerotic lesions. LOX-1 specific inhibitors, urgently necessary to reduce the rate of atherosclerotic and inflammation processes, are not yet available. We have designed and synthesized a new modified oxidized phospholipid, named PLAzPC, which plays to small scale the ligand-receptor recognition scheme. Molecular docking simulations confirm that PLAzPC disables the hydrophobic component of the ox-LDL recognition domain and allows the interaction of the L-lysine backbone charged groups with the solvent and with the charged/ polar residues located around the edges of the LOX-1 hydrophobic tunnel. Binding assays, in a cell model system expressing human LOX-1 receptors, confirm that PLAzPC markedly inhibits ox-LDL binding to LOX-1 with higher efficacy compared to previously identified inhibitors.

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“…LOX-1 is heavily modified by N -linked carbohydrate, and experiments with tunicamycin-treated cells have suggested that this N -linked glycosylation may contribute to OxLDL binding (87). Interestingly, Xie et al (88) recently reported that human LOX-1 functions as a disulfide-linked homodimer at the cell surface. In addition to acting as a membrane receptor for OxLDL, soluble forms of LOX-1 have been identified that are secreted by tumor necrosis factor-␣ -stimulated endothelial cells (89).…”

Section: Lox-1mentioning

confidence: 99%

Thematic review series: The Immune System and Atherogenesis. Recent insights into the biology of macrophage scavenger receptors

Greaves

Gordon

2005

Journal of Lipid Research

189

115

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Scavenger receptors were originally defined by their ability to bind and internalize modified lipoproteins. Macrophages express at least six structurally different cell surface receptors for modified forms of LDL that contribute to foam cell formation in atherosclerosis. In addition to their role in the pathology of atherosclerosis, macrophage scavenger receptors, especially SR-A, play critical roles in innate immunity, apoptotic cell clearance, and tissue homeostasis. In this review, we highlight recent advances in understanding the biology of macrophage scavenger receptors as pattern recognition receptors for both infectious nonself (pathogens) and modified self (apoptotic cells and modified LDL). We critically evaluate the potential of scavenger receptors and their ligands as targets for therapeutic intervention in human disease. -Greaves, D. R., and S. Gordon. MACROPHAGE-DERIVED FOAM CELLSFatty streaks, which are the earliest forms of atherosclerotic lesion visible in the artery wall, consist almost entirely of macrophage-derived foam cells (1-3). Monocytes that have been recruited to the subendothelial space at sites of endothelial cell activation differentiate into macrophages and express a range of scavenger receptors, which mediate the endocytic uptake of modified forms of LDL (4). Brown, Goldstein, and colleagues (5, 6) coined the term "scavenger receptor" to distinguish the uptake of modified LDL by macrophages from LDL uptake via the classical LDL receptor, which is feedback inhibited by the accumulation of cholesterol within the cell. Molecular cloning and biochemical characterization of the cellular receptors that mediate the uptake of modified forms of LDL have revealed an unexpectedly large number of endocytic receptors (7, 8). These membrane proteins have widely different structures, and all the scavenger receptors characterized to date bind a number of ligands of biological importance other than modified LDL. Even more puzzling is the recently described scavenger receptor SR-PSOX (scavenger receptor that binds phosphatidylserine and oxidized lipoprotein), which can act both as a receptor [for oxidized LDL (OxLDL)] and as a ligand (the membranebound CXC chemokine, CXCL16).Their lack of feedback inhibition by intracellular cholesterol has made macrophage scavenger receptors scapegoats for the development of macrophage foam cell formation in the artery wall, but it is important to recognize that other metabolic pathways play an important role in the development of cholesteryl ester deposits in macrophage foam cells. Modified apolipoprotein B (apoB)-containing lipoproteins taken up via scavenger receptors are delivered to lysosomes and hydrolyzed to release free cholesterol and fatty acids. The conversion of free cholesterol into cholesteryl esters in macrophages is catalyzed by the enzyme ACAT, and free cholesterol can be converted by the mitochondrial enzyme Cyp27 into 27-hydroxycholesterol, one of several oxysterols that activate changes in macrophage foam cell transcription via the nuc...

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Human Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Functions as a Dimer in Living Cells

Cited by 51 publications

References 24 publications

Human MICL (CLEC12A) is differentially glycosylated and is down‐regulated following cellular activation

Human MICL (CLEC12A) is differentially glycosylated and is down‐regulated following cellular activation

Design of a novel LOX-1 receptor antagonist mimicking the natural substrate

Thematic review series: The Immune System and Atherogenesis. Recent insights into the biology of macrophage scavenger receptors

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