Ro 60 functions as a receptor for β<sub>2</sub>‐glycoprotein I on apoptotic cells

Reed, Joanne H.; Giannakopoulos, Bill; Jackson, Michael; Krilis, Steven A.; Gordon, Tom P.

doi:10.1002/art.24361

Cited by 36 publications

(35 citation statements)

References 36 publications

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“…Because it does not span the membrane, the way it works remains to be established (55). Finally, data has just been published (22) that b2-gpI binds to the 60-kDa Ro protein on apoptotic cells.…”

Section: Discussionmentioning

confidence: 99%

“…This electrostatic symmetry needs to be reinforced by a sound link between 2 aa sequences, one in the cofactor and another in unknown receptors on the membrane. Candidates include megalin (19), annexin A2 (20), aplipoprotein E receptor 2 (21), and Ro60 exposed on apoptotic blebs (22). The binding of stable b2-gpI-containing immune complexes to any of these receptors (23) is assumed to trigger a cascade of kinases (24) conveyed through dynamic assemblies of cholesterol and cholera toxin B (CTB)-binding ganglioside M1 termed lipid rafts (LRs).…”

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confidence: 99%

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TLR2 Is One of the Endothelial Receptors for β2-Glycoprotein I

Alard

Gaillard

Daridon

et al. 2010

The Journal of Immunology

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During the antiphospholipid syndrome, β2-gpI interacts with phospholipids on endothelial cell (EC) surface to allow the binding of autoantibodies. However, induced-pathogenic intracellular signals suggest that β2-gpI associates also with a receptor that is still not clearly identified. TLR2 and TLR4 have long been suspected, yet interactions between TLRs and β2-gpI have never been unequivocally proven. The aim of the study was to identify the TLR directly involved in the binding of β2-gpI on EC surface. β2-gpI was not synthesized and secreted by ECs in vitro, but rather taken up from FCS. This uptake occurred through association with TLR2 and TLR4 which partitioned together in the lipid rafts of ECs. After coimmunoprecipitation, mass-spectrometry identification of peptides demonstrated that TLR2, but not TLR4, was implicated in the β2-gpI retention. These results were further confirmed by plasmon resonance-based studies. Finally, siRNA were used to obtain TLR2-deficient ECs that lost their ability to bind biotinylated β2-gpI and to trigger downstream phosphorylation of kinases and activation of NFκB. TLR4 may upregulate TLR2 expression, thereby contributing to β2-gpI uptake. However, our data demonstrate that direct binding of β2-gpI on EC surface occurs through direct interaction with TLR2. Furthermore, signaling for anti–β2-gpI may be envisioned as a multiprotein complex concentrated in lipid rafts on the EC membrane.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

TLR2 Is One of the Endothelial Receptors for β2-Glycoprotein I

Alard

Gaillard

Daridon

et al. 2010

The Journal of Immunology

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“…2): UCHL5 (MIM: *610667) encodes a deubiquitinating enzyme known to associate with 26 proteasomes (Hamazaki et al, 2006), and found unregulated in uterine cervical neoplasms (Rolen et al, 2006); TROVE2 (MIM: *600063) encodes a protein that functions as a receptor for beta(2)-glycoprotein I on apoptotic cells (Reed et al, 2009); GLRX2 (MIM: *606820) has been recognized to encode an important redox regulator in mammalian organs including heart (Nagy et al, 2008); and B3GALT2 (MIM: *603018), an overlapping RNA transcribed in opposite direction to CDC73, encodes a protein that functions in Nlinked glycoprotein glycosylation. No other clinical signs apart from those fitting the HPT-JT syndrome were found in this family, suggesting that all these genes are haplosufficient.…”

Section: First Gross Cdc73 Germline Deletionmentioning

confidence: 99%

Detection of the first gross CDC73 germline deletion in an HPT‐JT syndrome family

Cascón

Huarte-Mendicoa

Leandro‐García

et al. 2011

Genes Chromosomes & Cancer

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Hereditary primary hyperparathyroidism (HPT) may develop as a solitary endocrinopathy (FIHP) or as part of multiple endocrine neoplasia Type 1, multiple endocrine neoplasia Type 2A, or hereditary HPT-jaw tumor syndrome. Inactivating germline mutations of the tumor suppressor gene CDC73 account for 14 and 50% of all FIHP and HPT-JT patients, respectively, and have also been found in almost 20% of apparently sporadic parathyroid carcinoma patients. Although more than 60 independent germline mutations have been described, to date no rearrangement affecting the CDC73 locus has been identified. By means of multiplex-PCR we found a large germline deletion affecting the whole gene in a two-generation HPT-JT family. Subsequently array-CGH and specific PCR analysis determined that the mutation spanned ∼ 547 kb, and included four additional genes: TROVE2, GLRX2, B3GALT2, and UCHL5. Although no clear mutation-specific phenotype was found associated to the presence of the mutation, further studies are needed to assess whether the loss of the neighboring genes could modify the phenotype of carriers. There was complete absence of nuclear staining in the two HPT-JT-related tumors available. The finding of the first rearrangement affecting the CDC73 gene warrants screening for this tumor suppressor gene inactivation mechanism not only in high-risk CDC73 point mutation-negative HPT-JT families, but also in FIHP patients.

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“…The function of ␤2GPI remains uncertain, although it is thought to play a role in apoptotic cell clearance and coagulation through multiple interactions with serine proteases, anionic phospholipid, and cell-surface receptors. [13][14][15][16][17][18][19][20] It is found in relatively high concentrations in circulating plasma (4M) and is also found within atherosclerotic plaque lesions, 21 although the function of ␤2GPI relating to atherosclerosis has not been elucidated. The antiphospholipid syndrome is an autoimmune condition characterized by pathogenic circulating anti-␤2GPI antibodies.…”

Section: Introductionmentioning

confidence: 99%

Naturally occurring free thiols within β2-glycoprotein I in vivo: nitrosylation, redox modification by endothelial cells, and regulation of oxidative stress–induced cell injury

Ioannou

Zhang

Passam

et al. 2010

Blood

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␤2-Glycoprotein I (␤2GPI) is an evolutionary conserved, abundant circulating protein. Although its function remains uncertain, accumulated evidence points toward interactions with endothelial cells and components of the coagulation system, suggesting a regulatory role in vascular biology. Our group has shown that thioredoxin 1 (TRX-1) generates free thiols in ␤2GPI, a process that may have a regulatory role in platelet adhesion. This report extends these studies and shows for the first time evidence of ␤2GPI with free thiols in vivo in both multiple human and murine serum samples. To explore how the vascular surface may modulate the redox status of ␤2GPI, unstimulated human endothelial cells and EAhy926 cells are shown to be capable of amplifying the effect of free thiol generation within ␤2GPI. Multiple oxidoreductase enzymes, such as endoplasmic reticulum protein 46 (ERp 46) and TRX-1 reductase, in addition to protein disulfide isomerase are secreted on the surface of endothelial cells. Furthermore, one or more of these generated free thiols within ␤2GPI are also shown to be nitrosylated. Finally, the functional significance of these findings is explored, by showing that free thiol-containing ␤2GPI has a powerful effect in protecting endothelial cells and EAhy926 cells from oxidative stress-induced cell death. IntroductionThioredoxin 1 (TRX-1) is a ubiquitous, 12-kDa oxidoreductase enzyme whose multiple intracellular functions include reducing protein disulfides, scavenging oxygen free radicals, and redox regulation of signaling pathways involved in cell growth, apoptosis, and inflammation. 1 TRX-1 requires nitrosylation of the unpaired cysteine (Cys69) thiol to mediate key intracellular functions. 2 S-nitrosylation of thiols has been implicated as being important in several multisystemic physiologic and pathologic processes pertaining to hemostasis and vascular disease. 3 In addition to being a key intracellular molecule, TRX-1 is an enzyme also found in circulating plasma. It is released from cells in response to oxidative stress 4,5 and is found at higher levels in the circulation in a variety of acute and chronic inflammatory or metabolic conditions associated with an increase in systemic oxidative stress load. [6][7][8] Studies have shown that exogenous administration of TRX-1 exerts a protective role in animal models of high oxidative stress such as smoking and rheumatoid arthritis, 9,10 both of which represent risk factors for cardiovascular morbidity in humans. 11 Oxidative stress is known to be associated with vascular pathology in terms of promoting atherosclerotic plaque development, rupture and atherothrombosis. 12 However, the extracellular mechanism through which elevated TRX-1 may mediate a protective effect against oxidative stress-induced vascular injury has not been fully delineated.␤ 2 -Glycoprotein I (␤2GPI) is an evolutionary conserved 50-kDa plasma protein. The function of ␤2GPI remains uncertain, although it is thought to play a role in apoptotic cell clearance and coagulation through m...

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Ro 60 functions as a receptor for β₂‐glycoprotein I on apoptotic cells

Cited by 36 publications

References 36 publications

TLR2 Is One of the Endothelial Receptors for β2-Glycoprotein I

TLR2 Is One of the Endothelial Receptors for β2-Glycoprotein I

Detection of the first gross CDC73 germline deletion in an HPT‐JT syndrome family

Naturally occurring free thiols within β2-glycoprotein I in vivo: nitrosylation, redox modification by endothelial cells, and regulation of oxidative stress–induced cell injury

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Ro 60 functions as a receptor for β2‐glycoprotein I on apoptotic cells

Cited by 36 publications

References 36 publications

TLR2 Is One of the Endothelial Receptors for β2-Glycoprotein I

TLR2 Is One of the Endothelial Receptors for β2-Glycoprotein I

Detection of the first gross CDC73 germline deletion in an HPT‐JT syndrome family

Naturally occurring free thiols within β2-glycoprotein I in vivo: nitrosylation, redox modification by endothelial cells, and regulation of oxidative stress–induced cell injury

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Ro 60 functions as a receptor for β₂‐glycoprotein I on apoptotic cells