Year: 2019
Type: preprint
Abstract: Background Autoinflammatory diseases (AID) result from dysregulation of the first lines of innate immune responses. Recently, development of high throughput genome sequencing technology led to the rapid emergence of important knowledge in the genetic field. About 20 genes have been identified so far in monogenic forms of distinct AID. However, 70-90 % of patients with AID remain without genetic diagnosis. Objective We report the identification and characterization of a mutation in the C-terminal region of the Rho GTPase Cdc42 in a patient presenting a severe autoinflammatory phenotype. Methods We have analyzed the consequences of the mutation on the subcellular localization of the Cdc42 protein using imaging techniques. Molecular studies were performed using proteomic and biochemical experiments to provide mechanistic bases of the observed defects. Functional assays were also conducted using flow cytometry and cytokine production measurements. Results We show that mutant Cdc42 is trapped in the Golgi apparatus due to the aberrant addition of a palmitate that both enhances the interaction of mutant Cdc42 with Golgi membranes and inhibit its extraction by GDP dissociation inhibitor (GDI), thus impairing its cytosol/membrane shuttling. At the functional level, mutant Cdc42 fails to sustain actin filaments polymerization and induces an exacerbated profile of pro-inflammatory cytokine production due to increased NF-κB activation. Conclusions Our study now provides a molecular explanation for mutations that have been identified recently in our AID patient and others in the C-terminal part of Cdc42. Mutations located in this region of Cdc42 impair the intracellular localization of Cdc42, preventing its interaction with the plasma membrane. Thus, our results definitively link mutations in the CDC42 gene to a complex immune-hemato-autoinflammatory phenotype in humans.
DOI: 10.1101/808782
Authors: Bahia Bekhouche, Aurore Tourville, Yamini Ravichandran, Rachida Tacine, Laurence Abrami, Michael Dussiot, Andrea Khau-Dancasius, Olivia Boccara, Meriem Khirat, Marianne Mangeney, Nathalia Bellon, Sylvie Fraitag, Smail Hadj-Rabia, Stéphane Blanche, Anne Puel, Sandrine Etienne-Manneville, F. Gisou van der Goot, Jacqueline Cherfils, Olivier Hermine, Jean-Laurent Casanova, Christine Bodemer, Asma Smahi, Jérôme Delon
Institutions: Centre National de la Recherche Scientifique, Inserm, Sorbonne Paris Cité, Institut des Maladies Génétiques Imagine, Université Paris Descartes, Université Paris Cité, Institut Cochin, Institut Pasteur, Sorbonne Université, Biologie cellulaire physiologique et pathologique, École Polytechnique Fédérale de Lausanne, Hôpital Necker-Enfants Malades, Institut Necker Enfants Malades, Assistance Publique – Hôpitaux de Paris, Laboratoire d'hématologie, École Normale Supérieure Paris-Saclay, Laboratoire de Biologie et Pharmacologie Appliquée, Howard Hughes Medical Institute, Rockefeller University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: European Commission, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Ligue Contre le Cancer, Centre National de la Recherche Scientifique, Université Paris Descartes, Société Française de Dermatologie et de Pathologie Sexuellement Transmissible
OpenAlex ID: W2981158051