Differential but Competitive Binding of Nogo Protein and Class I Major Histocompatibility Complex (MHCI) to the PIR-B Ectodomain Provides an Inhibition of Cells

Abstract

Binding of class I MHC molecules (MHCI) to an inhibitory receptor, PIR-B, expressed on B cells and myeloid cells provides; also known as class I H-2 and HLA in mice and humans, respectively) (6). Because MHCI are expressed ubiquitously, the binding to MHCI causes PIR-B to deliver a constitutive inhibitory signal via recruitment of tyrosine phosphatase, Src homology 2 domain-containing tyrosine phosphatase-1 (7-9), whose substrates are critical cytosolic signaling molecules such as Bruton's tyrosine kinase (10). Similar to other stimulatory and inhibitory receptor pairs with shared ligand-binding specificities (11), PIR-B expression usually takes place concomitantly with that of the activating-type isoform PIR-A although the physiological role of PIR-A in the immune system remains largely unknown.Recent unexpected findings have revealed additional inhibitory roles of PIR-B in synaptic plasticity (12) and axonal regeneration (13) in the neuronal system. In mice lacking functional PIR-B, the cortical ocular dominance plasticity is more robust, indicating that PIR-B functions to limit the extent of experience-dependent plasticity in the visual cortex and suggesting that it may function broadly to stabilize neuronal circuits (12). Surprisingly, it has also been reported (13) that PIR-B can bind to three axonal outgrowth inhibitory proteins in oligodendrocytes, i.e. neurite outgrowth inhibitor protein (Nogo) (14), myelin-associated glycoprotein (MAG) (15, 16), and oligodendrocyte myelin glycoprotein (OMgp) (17), like the Nogo receptor does (18,19). Interfering with PIR-B activity, either with antibodies or by genetic deletion of the cytoplasmic portion of PIR-B, partially reverses the neurite inhibition by Nogo, MAG, and OMgp, implying that PIR-B mediates the regeneration blocking of axons (13).Given the two kinds of physiological ligands for PIR-B, i.e. MHCI and neurite outgrowth inhibitor proteins, we were

Soluble LILRA3 promotes neurite outgrowth and synapses formation through a high-affinity interaction with Nogo 66

“…8A-C). Although methodological differences should be accounted for and future concurrent comparative studies are required, our SPR results indicate that the binding affinity of Nogo 66 to LILRA3 is 10-100 times higher than its binding to PIRB (Matsushita et al, 2011) or NgR1 (Lauren et al, 2007). These properties are consistent with a typical soluble competitive antagonist with broad functional specificity.…”

The Expanding Spectrum of Ligands for Leukocyte Ig-like Receptors

“…Nonetheless, PIRB is expressed on particular neurons, and subsequent studies by the Shatz group and others (60)(61)(62)(63) have shown that PIRB regulates axon regeneration in a SHP-dependent manner and even neural stem cell survival. PIRB has six Ig domains, and, similar to LILRB2, the first two Ig domains mediate the interaction with mouse MHC-I molecules (64). In contrast, the third to sixth domains mediate the strongest binding with Nogo, but the first two alone also interact but with a 10-fold lower dissociation constant (64).…”

“…PIRB has six Ig domains, and, similar to LILRB2, the first two Ig domains mediate the interaction with mouse MHC-I molecules (64). In contrast, the third to sixth domains mediate the strongest binding with Nogo, but the first two alone also interact but with a 10-fold lower dissociation constant (64). Takai et al (64) used surface plasmon resonance to define binding constants with Nogo and PIRB that are submicromolar.…”

“…In contrast, the third to sixth domains mediate the strongest binding with Nogo, but the first two alone also interact but with a 10-fold lower dissociation constant (64). Takai et al (64) used surface plasmon resonance to define binding constants with Nogo and PIRB that are submicromolar. Furthermore, they found that Nogo competes with MHC-I for binding to PIRB (64).…”

Endoplasmic Protein Nogo-B (RTN4-B) Interacts with GRAMD4 and Regulates TLR9-Mediated Innate Immune Responses

“…For example, studies conducted using Nogo-A/B-deficient (nogo-A/B 2⁄2 ) mice revealed that Nogo-B in lung epithelia regulates Th2-mediated inflammation, and endothelial Nogo-B regulates leukocyte transmigration to sites of inflammation (26)(27)(28). Although the links between Nogo and inflammatory responses are emerging, the role of Nogo in immune cells is virtually unknown.…”