title: Identification of the low density lipoprotein (LDL) receptor-related protein-1 interactome in central nervous system myelin suggests a role in the clearance of necrotic cell debris.
abstract: In the central nervous system (CNS), fast neuronal signals are facilitated by the oligodendrocyte-produced myelin sheath. Oligodendrocyte turnover or injury generates myelin debris that is usually promptly cleared by phagocytic cells. Failure to remove dying oligodendrocytes leads to accumulation of degraded myelin, which, if recognized by the immune system, may contribute to the development of autoimmunity in diseases such as multiple sclerosis. We recently identified low density lipoprotein receptor-related protein-1 (LRP1) as a novel phagocytic receptor for myelin debris. Here, we report characterization of the LRP1 interactome in CNS myelin. Fusion proteins were designed corresponding to the extracellular ligand-binding domains of LRP1. LRP1 partners were isolated by affinity purification and characterized by mass spectrometry. We report that LRP1 binds intracellular proteins via its extracellular domain and functions as a receptor for necrotic cells. Peptidyl arginine deiminase-2 and cyclic nucleotide phosphodiesterase are novel LRP1 ligands identified in our screen, which interact with full-length LRP1. Furthermore, the extracellular domain of LRP1 is a target of peptidyl arginine deiminase-2-mediated deimination in vitro. We propose that LRP1 functions as a receptor for endocytosis of intracellular components released during cellular damage and necrosis.
authors.affiliation: Department of Neuroscience and Center for Brain Immunology and Glia, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Fernandez-Castaneda
authors.forename: Sanja
authors.initials: S
authors.lastname: Arandjelovic
authors.forename: Travis L
authors.initials: TL
authors.lastname: Stiles
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Schlobach
authors.forename: Kerri A
authors.initials: KA
authors.lastname: Mowen
authors.forename: Steven L
authors.initials: SL
authors.lastname: Gonias
authors.forename: Alban
authors.initials: A
authors.lastname: Gaultier
mesh_terms: D000818:Animals; D017209:Apoptosis; D002490:Central Nervous System / Q000378:metabolism*; D002956:Citrulline / Q000737:chemistry; D003001:Cloning, Molecular; D004705:Endocytosis; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D009103:Multiple Sclerosis / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D009336:Necrosis; D010587:Phagocytosis; D040901:Proteomics / Q000379:methods
chemical_list: D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D049452:Green Fluorescent Proteins; D002956:Citrulline; D005982:Glutathione Transferase