title: A polyglutamic acid motif confers IL-27 hydroxyapatite and bone-binding properties.
abstract: The p28 subunit of the composite cytokine IL-27 comprises a polyglutamic acid domain, which is unique among type I cytokines. This domain is very similar to the acidic domain known to confer hydroxyapatite (HA)-binding properties and bone tropism to bone sialoprotein. We observed IL-27 binding to HA, in accordance with previous studies reporting successful p28 HA chromatography. The IL-27 polyglutamic acid domain is located in a flexible inter-α helix loop, and HA-bound IL-27 retained biological activity. Using IL-27 alanine mutants, we observed that the p28 polyglutamic acid domain confers HA- and bone-binding properties to IL-27 in vitro and bone tropism in vivo. Because IL-27 is a potent regulator of cells residing in endosteal bone marrow niches such as osteoclasts, T regulatory, memory T, plasma, and stem cells, this specific property could be beneficial for therapeutic applications. IL-27 has potent antitumoral and antiosteoclastogenic activities. It could therefore also be useful for therapies targeting hematologic cancer or solid tumors metastasis with bone tropism. Furthermore, these observations suggest that polyglutamic motifs could be grafted onto other type I cytokine inter-α helix loops to modify their pharmacological properties.
authors: Département de Pharmacologie, Université de Montréal, Montreal, Quebec H3T1J4, Canada.
authors: Aurélie Jeanne
authors: AJ
authors: Tormo
authors: Linda Ann
authors: LA
authors: Beaupré
authors: Greg
authors: G
authors: Elson
authors: Sandrine
authors: S
authors: Crabé
authors: Jean-François
authors: JF
authors: Gauchat
mesh_terms: D020816:Amino Acid Motifs / Q000276:immunology; D000818:Animals; D001853:Bone Marrow / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology / Q000637:transplantation; D002478:Cells, Cultured; D017886:Durapatite / Q000737:chemistry* / Q000378:metabolism; D005260:Female; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000276:immunology / Q000378:metabolism; D011099:Polyglutamic Acid / Q000737:chemistry* / Q000235:genetics / Q000627:therapeutic use; D011485:Protein Binding / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D007378:Interleukins; C464565:MYDGF protein, human; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D011099:Polyglutamic Acid; D017886:Durapatite