Nogo receptor antagonist LOTUS exerts suppression on axonal growth‐inhibiting receptor PIR‐B

• Published in: Journal of neurochemistry Vol. 155; no. 3; pp. 285 - 299
• Main Authors: Kurihara, Yuji, Takai, Toshiyuki, Takei, Kohtaro
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-11-2020
• Subjects: Animals; Animals, Newborn; Antibodies; axonal growth inhibition; Axonogenesis; Axons; Axons - drug effects; Axons - metabolism; Binding; Blocking antibodies; Cells, Cultured; Central nervous system; Chlorocebus aethiops; COS Cells; Dorsal roots; Female; Growth cones; HEK293 Cells; Humans; Immunocytochemistry; lateral olfactory tract usher substance; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myelin; Nerve Tissue Proteins - pharmacology; Neurons; Nogo protein; Nogo Receptor 1 - antagonists & inhibitors; Nogo Receptor 1 - metabolism; Nogo‐A; Olfactory Bulb - drug effects; Olfactory Bulb - metabolism; paired immunoglobulin‐like receptor‐B; Polymerase chain reaction; Protein interaction; Proteins; Receptor mechanisms; Receptors; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - metabolism; Regeneration; Reverse transcription; paired immunoglobulin-like receptor-B; Nogo-A; axonal growth inhibition; lateral olfactory tract usher substance
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15013

Damaged axons in the adult mammalian central nervous system have a restricted regenerative capacity mainly because of Nogo protein, which is a major myelin‐associated axonal growth inhibitor with binding to both receptors of Nogo receptor‐1 (NgR1) and paired immunoglobulin‐like receptor (PIR)‐B. Lateral olfactory tract usher substance (LOTUS) exerts complete suppression of NgR1‐mediated axonal growth inhibition by antagonizing NgR1. However, the regulation of PIR‐B functions in neurons remains unknown. In this study, protein–protein interactions analyses found that LOTUS binds to PIR‐B and abolishes Nogo‐binding to PIR‐B completely. Reverse transcription‐polymerase chain reaction and immunocytochemistry revealed that PIR‐B is expressed in dorsal root ganglions (DRGs) from wild‐type and Ngr1‐deficient mice (male and female). In these DRG neurons, Nogo induced growth cone collapse and neurite outgrowth inhibition, but treatment with the soluble form of LOTUS completely suppressed them. Moreover, Nogo‐induced growth cone collapse and neurite outgrowth inhibition in Ngr1‐deficient DRG neurons were neutralized by PIR‐B function‐blocking antibodies, indicating that these Nogo‐induced phenomena were mediated by PIR‐B. Our data show that LOTUS negatively regulates a PIR‐B function. LOTUS thus exerts an antagonistic action on both receptors of NgR1 and PIR‐B. This may lead to an improvement in the defective regeneration of axons following injury.
Myelin‐associated axonal growth inhibitors such as Nogo protein bind to both receptors of Nogo receptor‐1 (NgR1) and paired immunoglobulin‐like receptor (PIR)‐B, leading to a regenerative failure of damaged axons in the adult mammalian central nervous system. We previously reported that lateral olfactory tract usher substance (LOTUS) suppresses NgR1‐mediated axonal growth inhibition. In this study, we found that LOTUS interacts with PIR‐B, inhibits Nogo‐binding to PIR‐B, and thereby suppresses PIR‐B‐mediated axonal growth inhibition. These findings show that LOTUS exerts an antagonistic activity on PIR‐B, suggesting that LOTUS may enhance the regenerative capacity of injured axons.