Serum Gp96 is a chaperone of complement-C3 during graft-versus-host disease.

Antoine Seignez 1, 2, 3 Anne-Laure Joly 1, 3 Killian Chaumonnot 1, 3 Adonis Hazoumé 1, 3 Michel Sanka 1, 3 Guillaume Marcion 1, 3 Christophe Boudesco 1, 3 Arlette Hammann 1, 3 Renaud Seigneuric 1, 3 Gaetan Jégo 1, 3 Patrick Ducoroy 4 Patrice Delarue 5 Patrick Senet 5 Cristina Castilla-Llorente 6 Eric Solary 7, 6 Marie-Agnès Durey 8, 9 Marie-Thérèse Rubio 10, 11 Olivier Hermine 12, 13 Evelyne Kohli 1, 2, 3 Carmen Garrido 14, 1, 3, *
* Auteur correspondant
1 LabEx LipSTIC - Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer
2 CHU Dijon
3 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
4 CLIPP - Plate-forme Protéomique CLIPP - Clinical and Innovation Proteomic Platform [Dijon]
FEMTO-ST - Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies, ICMUB - Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon]
5 LICB - Laboratoire Interdisciplinaire Carnot de Bourgogne [Dijon]
6 IGR - Institut Gustave Roussy
7 Hématopoïèse normale et pathologique
8 Service d'Immunologie Clinique, Hôpital Européen Georges Pompidou, Paris
9 UPD5 - Université Paris Descartes - Paris 5
10 Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine]
11 CR Saint-Antoine - Centre de Recherche Saint-Antoine
12 CHRI - Cytokines, hématopoïèse et réponse immune
13 CHU Necker - Enfants Malades [AP-HP]
14 CRLCC - CGFL - Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc
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.
Keywords : Shock-Protein Gp96 Cell Transplantation Glycoprotein 96 Component C3 In-Vivo Differentiation Erythropoiesis Inhibitor Therapy Gata-1
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01547271
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : lundi 26 juin 2017 - 15:13:24
Dernière modification le : mercredi 21 mars 2018 - 18:57:35

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UNIV-FCOMTE | UNIV-BM | INRA | CGFL | UNIV-BM-THESE | FNCLCC | LNC-UMR866 | INC-CNRS | PSL | FEMTO-ST | U938 | UPMC | UNIV-PARIS5 | USPC | UNIV-PARIS-SACLAY | ICMUB | IGR

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Antoine Seignez, Anne-Laure Joly, Killian Chaumonnot, Adonis Hazoumé, Michel Sanka, et al.. Serum Gp96 is a chaperone of complement-C3 during graft-versus-host disease.. JCI Insight, 2017, 2 (6), pp.e90531. 〈https://insight.jci.org/articles/view/90531〉. 〈10.1172/jci.insight.90531〉. 〈hal-01547271〉

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