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

Antoine Seignez; Anne-Laure Joly; Killian Chaumonnot; Adonis Hazoumé; Michel Sanka; Guillaume Marcion; Christophe Boudesco; Arlette Hammann; Renaud Seigneuric; Gaetan Jégo; Patrick Ducoroy; Patrice Delarue; Patrick Senet; Cristina Castilla-Llorente; Eric Solary; Marie-Agnès Durey; Marie-Thérèse Rubio; Olivier Hermine; Evelyne Kohli; Carmen Garrido

doi:10.1172/jci.insight.90531

Article dans une revue

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 (UMR 6174), 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 UMRS893 - Centre de Recherche Saint-Antoine

12 CHRI - Cytokines, hématopoïèse et réponse immune

13 CHU Necker - Enfants Malades [AP-HP]

14 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]

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 : Differentiation In-Vivo Component C3 Glycoprotein 96 Cell Transplantation Shock-Protein Gp96 Erythropoiesis Inhibitor Therapy Gata-1

Type de document :

Article dans une revue

Domaine :

Sciences du Vivant [q-bio] / Médecine humaine et pathologie

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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01547271
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Soumis le : lundi 26 juin 2017 - 15:13:24
Dernière modification le : jeudi 13 janvier 2022 - 12:00:21

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

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