title: Heat shock protein 70 (Hsp70) interacts with the Notch1 intracellular domain and contributes to the activity of Notch signaling in myelin-reactive CD4 T cells.
abstract: Notch receptors (Notch1-4) are involved in the differentiation of CD4 T cells and the development of autoimmunity. Mechanisms regulating Notch signaling in CD4 T cells are not fully elucidated. In this study we investigated potential crosstalk between Notch pathway molecules and heat shock protein 70 (Hsp70), the major intracellular chaperone involved in the protein transport during immune responses and other stress conditions. Using Hsp70(-/-) mice we found that Hsp70 is critical for up-regulation of NICD1 and induction of Notch target genes in Jagged1- and Delta-like1-stimulated CD4 T cells. Co-immunoprecipitation analysis of wild-type CD4 T cells stimulated with either Jagged1 or Delta-like1 showed a direct interaction between NICD1 and Hsp70. Both molecules co-localized within the nucleus of CD4 T cells stimulated with Notch ligands. Molecular interaction and nuclear colocalization of NICD1 and Hsp70 were also detected in CD4 T cells reactive against myelin oligodendrocyte glycoprotein (MOG)35-55, which showed Hsp70-dependent up-regulation of both NICD1 and Notch target genes. In conclusion, we demonstrate for the first time that Hsp70 interacts with NICD1 and contributes to the activity of Notch signaling in CD4 T cells. Interaction between Hsp70 and NICD1 may represent a novel mechanism regulating Notch signaling in activated CD4 T cells.
authors.affiliation: Department of Neurology, Medical University of Lodz, Kopcińskiego 22, 90-153 Lodz, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Juryńczyk
authors.affiliation: Department of Neurology, Medical University of Lodz, Kopcińskiego 22, 90-153 Lodz, Poland.
authors.forename: Przemysław
authors.initials: P
authors.lastname: Lewkowicz
authors.affiliation: Department of Neurology, Medical University of Lodz, Kopcińskiego 22, 90-153 Lodz, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Domowicz
authors.affiliation: Department of Neurology, Medical University of Lodz, Kopcińskiego 22, 90-153 Lodz, Poland.
authors.forename: Marcin P
authors.initials: MP
authors.lastname: Mycko
authors.affiliation: Department of Neurology, Medical University of Lodz, Kopcińskiego 22, 90-153 Lodz, Poland. Electronic address: kselmaj@afazja.am.lodz.pl.
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Selmaj
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D005620:Freund's Adjuvant / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D018840:HSP70 Heat-Shock Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; C497762:Notch1 protein, mouse; D010446:Peptide Fragments; D051881:Receptor, Notch1; C445081:myelin oligodendrocyte glycoprotein (35-55); D005620:Freund's Adjuvant
keywords: CD4(+) T cells; Heat shock proteins; Neuroimmunology; Notch signaling