RT Journal Article
SR Electronic
T1 A toxic palmitoylation on Cdc42 drives a severe autoinflammatory syndrome
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 808782
DO 10.1101/808782
A1 Bahia Bekhouche
A1 Aurore Tourville
A1 Yamini Ravichandran
A1 Rachida Tacine
A1 Laurence Abrami
A1 Michael Dussiot
A1 Andrea Khau-Dancasius
A1 Olivia Boccara
A1 Meriem Khirat
A1 Marianne Mangeney
A1 Nathalia Bellon
A1 Sylvie Fraitag
A1 Smail Hadj-Rabia
A1 Stéphane Blanche
A1 Anne Puel
A1 Sandrine Etienne-Manneville
A1 F. Gisou van der Goot
A1 Jacqueline Cherfils
A1 Olivier Hermine
A1 Jean-Laurent Casanova
A1 Christine Bodemer
A1 Asma Smahi
A1 Jérôme Delon
YR 2019
UL http://biorxiv.org/content/early/2019/10/17/808782.abstract
AB 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.