3 results on '"Christelle Reperant"'
Search Results
2. N-Glycosylation Deficiency Reduces the Activation of Protein C and Disrupts Endothelial Barrier Integrity
- Author
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Tiffany Pascreau, François Saller, Elsa P. Bianchini, Dominique Lasne, Arnaud Bruneel, Christelle Reperant, François Foulquier, Cécile V. Denis, Pascale De Lonlay, and Delphine Borgel
- Subjects
Congenital Disorders of Glycosylation ,Glycosylation ,Phosphotransferases (Phosphomutases) ,Thrombin ,Humans ,Endothelium ,Hematology ,Protein C - Abstract
Phosphomannomutase 2 (PMM2) deficiency is the most prevalent congenital disorder of glycosylation. It is associated with coagulopathy, including protein C deficiency. Since all components of the anticoagulant and cytoprotective protein C system are glycosylated, we sought to investigate the impact of an N-glycosylation deficiency on this system as a whole. To this end, we developed a PMM2 knockdown model in the brain endothelial cell line hCMEC/D3. The resulting PMM2low cells were less able to generate activated protein C (APC), due to lower surface expression of thrombomodulin and endothelial protein C receptor. The low protein levels were due to downregulated transcription of the corresponding genes (THBD and PROCR, respectively), which itself was related to downregulation of transcription regulators Krüppel-like factors 2 and 4 and forkhead box C2. PMM2 knockdown was also associated with impaired integrity of the endothelial cell monolayer—partly due to an alteration in the structure of VE-cadherin in adherens junctions. The expression of protease-activated receptor 1 (involved in the cytoprotective effects of APC on the endothelium) was not affected by PMM2 knockdown. Thrombin stimulation induced hyperpermeability in PMM2low cells. However, pretreatment of cells with APC before thrombin simulation was still associated with a barrier-protecting effect. Taken as a whole, our results show that the partial loss of PMM2 in hCMEC/D3 cells is associated with impaired activation of protein C and a relative increase in barrier permeability.
- Published
- 2022
3. DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity
- Author
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Charlotte Boussard, Laure Delage, Tania Gajardo, Alexandre Kauskot, Maxime Batignes, Nicolas Goudin, Marie-Claude Stolzenberg, Camille Brunaud, Patricia Panikulam, Quentin Riller, Maryse Moya-Nilges, Jean Solarz, Christelle Reperant, Béatrice Durel, Jean-Claude Bordet, Olivier Pellé, Corinne Lebreton, Aude Magerus-Chatinet, Vithura Pirabakaran, Pablo Vargas, Sébastien Dupichaud, Marie Jeanpierre, Angélique Vinit, Mohammed Zarhrate, Cécile Masson, Nathalie Aladjidi, Peter D Arkwright, Brigitte Bader-Meunier, Sandrine Baron Joly, Joy Benadiba, Elise Bernard, Dominique Berrebi, Christine Bodemer, Martin Castelle, Fabienne Charbit-Henrion, Marwa Chbihi, Agathe Debray, Philippe Drabent, Sylvie Fraitag, Miguel Hié, Judith Landman-Parker, Ludovic Lhermitte, Despina Moshous, Pierre Rohrlich, Frank M Ruemmele, Anne Welfringer-Morin, Maud Tusseau, Alexandre Belot, Nadine Cerf-Bensussan, Marie Roelens, Capucine Picard, Bénédicte Neven, Alain Fischer, Isabelle Callebaut, Mickaël Mathieu Ménager, Fernando E Sepulveda, Frédéric Adam, and Frédéric Rieux-Laucat
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Dedicator of cytokinesis (DOCK) proteins play a central role in actin cytoskeleton regulation. This is highlighted by the DOCK2 and DOCK8 deficiencies leading to actinopathies and immune deficiencies. DOCK8 and DOCK11 activate CDC42, a RHO-GTPase involved in actin cytoskeleton dynamics, among many cellular functions. The role of DOCK11 in human immune disease has been long suspected but has never been described so far. We studied eight male patients, from seven unrelated families, with hemizygous DOCK11 missense variants leading to reduced DOCK11 expression. The patients were presenting with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. Patients' platelets exhibited abnormal ultrastructural morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B lymphoblastoid cell lines (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls. Lastly, in line with the patients' autoimmune manifestations, we also observed abnormal regulatory T cells (Tregs) phenotype with profoundly reduced FOXP3 and IKZF2 expression. Moreover, we found a reduced T cell proliferation and an impaired STAT5B phosphorylation upon IL2 stimulation of the patients' lymphocytes. In conclusion, DOCK11 deficiency is a new X-linked immune-related actinopathy leading to impaired CDC42 activity and STAT5 activation, and associated with abnormal actin cytoskeleton remodeling as well as Tregs phenotype culminating in immune dysregulation and severe early-onset autoimmunity.
- Published
- 2023
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