title: Serum Gp96 is a chaperone of complement-C3 during graft-versus-host disease.
abstract: Better identification of severe acute graft-versus-host disease (GvHD) may improve the outcome of this life-threatening complication of allogeneic hematopoietic stem cell transplantation. GvHD induces tissue damage and the release of damage-associated molecular pattern (DAMP) molecules. Here, we analyzed GvHD patients (n= 39) to show that serum heat shock protein glycoprotein 96 (Gp96) could be such a DAMP molecule. We demonstrate that serum Gp96 increases in gastrointestinal GvHD patients and its level correlates with disease severity. An increase in Gp96 serum level was also observed in a mouse model of acute GvHD. This model was used to identify complement C3 as a main partner of Gp96 in the serum. Our biolayer interferometry, yeast two-hybrid and in silico modeling data allowed us to determine that Gp96 binds to a complement C3 fragment encompassing amino acids 749-954, a functional complement C3 hot spot important for binding of different regulators. Accordingly, in vitro experiments with purified proteins demonstrate that Gp96 downregulates several complement C3 functions. Finally, experimental induction of GvHD in complement C3-deficient mice confirms the link between Gp96 and complement C3 in the serum and with the severity of the disease.
authors.affiliation: INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.|CHU, Dijon, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Seignez
authors.affiliation: INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Joly
authors.affiliation: INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
authors.forename: Killian
authors.initials: K
authors.lastname: Chaumonnot
authors.affiliation: INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
authors.forename: Adonis
authors.initials: A
authors.lastname: Hazoumé
authors.affiliation: INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Sanka
authors.affiliation: INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Marcion
authors.affiliation: INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Boudesco
authors.affiliation: INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
authors.forename: Arlette
authors.initials: A
authors.lastname: Hammann
authors.affiliation: INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Seigneuric
authors.affiliation: INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.
authors.forename: Gaetan
authors.initials: G
authors.lastname: Jégo
authors.affiliation: Proteomic platform CLIPP, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ducoroy
authors.affiliation: UMR 6303 CNRS Institut Carnot, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Delarue
authors.affiliation: UMR 6303 CNRS Institut Carnot, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Senet
authors.affiliation: Institute Gustave Roussy, Université Paris-Sud 11, Villejuif, France.
authors.forename: Cristina
authors.initials: C
authors.lastname: Castilla-Llorente
authors.affiliation: Institute Gustave Roussy, Université Paris-Sud 11, Villejuif, France.|INSERM UMR1009, Institute Gustave Roussy, Villejuif, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.affiliation: Immunology Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Université Paris Descartes, Paris, France.
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Durey
authors.affiliation: Service d'Hématologie et Thérapie Cellulaire, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France.|INSERM UMR 938, Université Pierre et Marie Curie, Paris, France.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Rubio
authors.affiliation: Institut Imagine, UMR 8147, Université Paris Descartes, Sorbonne Paris-Cité; Hôpital Necker, Assistance publique-Hôpitaux de Paris, Paris, France.|Laboratoire d'Excellence des Globules Rouges (GR-ex), Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.affiliation: INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.|CHU, Dijon, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Kohli
authors.affiliation: INSERM UMR 866, Equipe labellisée, Ligue Nationale contre le Cancer, and Laboratoire d'Excellence LipSTIC, Dijon, France.|Université de Bourgogne Franche-Comté, LNC UMR 866, Dijon, France.|Anticancer Centre Georges-François Leclerc, Dijon, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D003167:Complement Activation; D003176:Complement C3 / Q000378:metabolism*; D006086:Graft vs Host Disease / Q000097:blood*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008562:Membrane Glycoproteins / Q000097:blood*; D051379:Mice; D008875:Middle Aged; D018832:Molecular Chaperones / Q000097:blood*; D055815:Young Adult
chemical_list: C038245:C3 protein, human; D003176:Complement C3; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; C053387:endoplasmin