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

Abstract

Objective. The autoantigens 60-kd Ro/SSA (Ro 60) and ␤ 2 -glycoprotein I (␤ 2 GPI) are both displayed on the surface membrane of apoptotic cells. Epitopespreading experiments have suggested that these autoantigens may be present as a complex on the apoptotic cell surface. This study was undertaken to investigate whether ␤ 2 GPI interacts with Ro 60 on apoptotic cells and alters the binding of anti-Ro 60 IgG.Methods. The interaction between soluble recombinant Ro 60 fragments and ␤ 2 GPI was investigated in vitro by direct and saturation binding assays using native human ␤ 2 GPI and recombinant domain deletion mutants. Binding of ␤ 2 GPI to early and late apoptotic cells was assessed by multiparameter flow cytometry, and specificity of binding was determined by competitive inhibition with soluble recombinant Ro 60 and anti-Ro 60 IgG.Results. The Ro 60 fragment expressing a surfaceexposed epitope (apotope) bound with high affinity (K d ‫؍‬ ϳ15 nM) to domain V of ␤ 2 GPI in vitro. Beta 2 -glycoprotein I bound to the surface of apoptotic cells in a dose-dependent manner and was blocked by the Ro 60 apotope fragment. In reciprocal competitive inhibition studies, ␤ 2 GPI blocked the binding of anti-Ro 60 autoantibodies to apoptotic cells in a dose-dependent manner, and anti-Ro 60 IgG inhibited the binding of ␤ 2 GPI.Moreover, ␤ 2 GPI showed a 2-fold increase in binding to apoptotic cells that overexpress Ro 60 on the surface.Conclusion. These results demonstrate that Ro 60 functions as a novel receptor for ␤ 2 GPI on the surface of apoptotic cells. The formation of Ro 60-␤ 2 GPI complexes may protect against anti-Ro 60 autoantibodymediated tissue injury.

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

“…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.…”

“…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).…”

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

“…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.…”

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

“…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.…”