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    Aberrant lipidation of a GTPase triggers a severe autoinflammatory syndrome

    Study directed by Jérôme Delon (Team Clotilde Randriamampita)

    An aberrant lipid modification of the CDC42 GTPase triggers a severe autoinflammatory syndrome


    The genetic bases responsible for many human pathologies remain largely unknown. In a study performed in collaboration with Asma Smahi (Imagine Institute) and published in the Journal of Allergy and Clinical Immunology, Jérôme Delon and his colleagues have just elucidated the molecular mechanisms behind a particularly severe autoinflammatory syndrome: an identified mutation on the small GTPase CDC42 triggers an aberrant palmitoylation of this protein and induces an overproduction of numerous pro-inflammatory cytokines.This work therefore reveals an unsuspected link between CDC42 signaling and inflammation. It also opens the way to new therapeutic avenues.


    Small GTPases of the RHO family such as RHOA, RAC1 and CDC42 are considered to act as molecular switches because they oscillate between a GDP-bound inactive state in the cytosol and a GTP-bound active state at the plasma membrane. This cytosol-membrane cycle is made possible by the presence of a geranyl-geranyl lipid anchor on a cysteine ​​localized in their C-terminal region. Ubiquitously expressed RHO GTPases are activated by a large number of cell surface receptors and engage multiple signaling pathways which control phenomena as crucial as cell migration, activation of immune cells and proliferation.

    Whole exome sequencing of a patient presenting a severe autoinflammatory syndrome (generalized pustular psoriasis) has allowed to identify a heterozygous mutation in the gene encoding for CDC42 which results in the substitution of an arginine into a cysteine ​​in the C-terminal part of the mutated protein. The authors have shown that this cysteine ​​is modified by addition of a palmitate which, in addition to normal geranyl-geranylation, results in a double lipid anchoring of the mutated CDC42 protein. This excess of lipidation causes the retention of the mutated CDC42 protein in the Golgi apparatus. From a functional perspective, this aberrant localization is responsible for a defect in actin filaments polymerization, an increase in nuclear translocation (Figure) and activation of NF-kB as well as an overproduction of pro-inflammatory cytokines such as IL-1beta, IL-6, IL-8, IL-18, IL-36 and TNF-alpha.


    Thus, this work reveals an unsuspected functional link between the CDC42 protein and the activation of the NF-kB signaling pathway responsible for the synthesis of numerous pro-inflammatory cytokines. These results also open the way to new therapeutic strategies for the various diseases related to defects in the subcellular localization of GTPases.


    Figure legend: Primary fibroblasts from the patient were stimulated with LPS and stained with an anti-NF-kB antibody (red). The nuclei were stained with Hoechst (blue). The nuclei in which NF-kB has translocated appear purple or pink.

    This study was funded by the Agence Nationale de la Recherche, the French Society of Dermatology and the ARC Foundation.



    A toxic palmitoylation of Cdc42 enhances NF-κB signaling and drives a severe autoinflammatory syndrome. Bekhouche B, Tourville A, Ravichandran Y, Tacine R, Abrami L, Dussiot M, Khau-Dancasius A, Boccara O, Khirat M, Mangeney M, Dingli F, Loew D, Boëda B, Jordan P, Molina TJ, Bellon N, Fraitag S, Hadj-Rabia S, Blanche S, Puel A, Etienne-Manneville S, van der Goot FG, Cherfils J, Hermine O, Casanova JL, Bodemer C, Smahi A, Delon J. J Allergy Clin Immunol. 2020 Apr 10:S0091-6749(20)30426-7. doi: 10.1016/j.jaci.2020.03.020.


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