title: HSC70 blockade by the therapeutic peptide P140 affects autophagic processes and endogenous MHCII presentation in murine lupus.
abstract: BACKGROUND
  The P140 phosphopeptide issued from the spliceosomal U1-70K small nuclear ribonucleoprotein protein displays protective properties in MRL/lpr lupus-prone mice. It binds both major histocompatibility class II (MHCII) and HSC70/Hsp73 molecules. P140 peptide increases MRL/lpr peripheral blood lymphocyte apoptosis and decreases autoepitope recognition by T cells.
  
  
  OBJECTIVE
  To explore further the mode of action of P140 peptide on HSC70+ antigen-presenting cells.
  
  
  METHODS
  P140 biodistribution was monitored in real time using an imaging system and by fluorescence and electron microscopy. Fluorescence activated cell sorting and Western blotting experiments were used to evaluate the P140 effects on autophagic flux markers.
  
  
  RESULTS
  P140 fluorescence accumulated especially in the lungs and spleen. P140 peptide reduced the number of peripheral and splenic T and B cells without affecting these cells in normal mice. Remaining MRL/lpr B cells responded normally to mitogens. P140 peptide decreased the expression levels of HSC70/Hsp73 chaperone and stable MHCII dimers, which are both increased in MRL/lpr splenic B cells. It impaired refolding properties of chaperone HSC70. In MRL/lpr B cells, it increased the accumulation of the autophagy markers p62/SQSTM1 and LC3-II, consistent with a downregulated lysosomal degradation during autophagic flux.
  
  
  CONCLUSIONS
  The study results suggest that after P140 peptide binding to HSC70, the endogenous (auto)antigen processing might be greatly affected in MRL/lpr antigen-presenting B cells, leading to the observed decrease of autoreactive T-cell priming and signalling via a mechanism involving a lysosomal degradation pathway. This unexpected mechanism might explain the beneficial effect of P140 peptide in treated MRL/lpr mice.
authors.affiliation: CNRS UPR9021, Institut de Biologie Moléculaire et Cellulaire, 67000 Strasbourg, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Page
authors.forename: Frédéric
authors.initials: F
authors.lastname: Gros
authors.forename: Nicolas
authors.initials: N
authors.lastname: Schall
authors.forename: Marion
authors.initials: M
authors.lastname: Décossas
authors.forename: Dominique
authors.initials: D
authors.lastname: Bagnard
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Briand
authors.forename: Sylviane
authors.initials: S
authors.lastname: Muller
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D001402:B-Lymphocytes / Q000473:pathology; D050883:HSC70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000187:drug effects* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D010446:Peptide Fragments / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D014018:Tissue Distribution
chemical_list: D050883:HSC70 Heat-Shock Proteins; D000949:Histocompatibility Antigens Class II; C494372:Hspa8 protein, mouse; D010446:Peptide Fragments; C535176:spliceosomal peptide P140