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Lateral olfactory tract usher substance (LOTUS) exerts complete suppression of NgR1\u2010mediated axonal growth inhibition by antagonizing NgR1. However, the regulation of PIR\u2010B functions in neurons remains unknown. In this study, protein\u2013protein interactions analyses found that LOTUS binds to PIR\u2010B and abolishes Nogo\u2010binding to PIR\u2010B completely. Reverse transcription\u2010polymerase chain reaction and immunocytochemistry revealed that PIR\u2010B is expressed in dorsal root ganglions (DRGs) from wild\u2010type and <jats:italic>Ngr1<\/jats:italic>\u2010deficient mice (male and female). In these DRG neurons, Nogo\u00a0induced growth cone collapse and neurite outgrowth inhibition, but treatment with the soluble form of LOTUS completely suppressed them. Moreover, Nogo\u2010induced growth cone collapse and neurite outgrowth inhibition in <jats:italic>Ngr1<\/jats:italic>\u2010deficient DRG neurons were neutralized by PIR\u2010B function\u2010blocking antibodies, indicating that these Nogo\u2010induced phenomena were mediated by PIR\u2010B. Our data show that LOTUS negatively regulates a PIR\u2010B function. LOTUS thus exerts an antagonistic action on both receptors of NgR1 and PIR\u2010B. This may lead to an improvement in the defective regeneration of axons following injury.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15013-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15013","type":"journal-article","created":{"date-parts":[[2020,3,23]],"date-time":"2020-03-23T08:42:47Z","timestamp":1584952967000},"page":"285-299","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Nogo receptor antagonist LOTUS exerts suppression on axonal growth\u2010inhibiting receptor PIR\u2010B"],"prefix":"10.1111","volume":"155","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1309-1143","authenticated-orcid":false,"given":"Yuji","family":"Kurihara","sequence":"first","affiliation":[{"name":"Molecular Medical Bioscience Laboratory Department of Medical Life Science Yokohama City University Graduate School of Medical Life Science Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4549-7116","authenticated-orcid":false,"given":"Toshiyuki","family":"Takai","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology Institute of Development, Aging and Cancer Tohoku University Sendai Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6938-0812","authenticated-orcid":false,"given":"Kohtaro","family":"Takei","sequence":"additional","affiliation":[{"name":"Molecular Medical Bioscience Laboratory Department of Medical Life Science 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