Equipe d’Accueil :

Team “Dynamics of the cytoskeleton-dependent responses of immune cells »
Intitulé de l’Unité : Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité
Nom du Responsable de l’Unité : Florence Niedergang
Nom des Responsables de l’Équipe : Jérôme Delon et Paolo Pierobon
Adresse : 22 rue Méchain, 75014 Paris
Responsable de l’encadrement : Jérôme Delon
Tél : 0140516640…………… Fax : ……………………… E-mail : jerome.delon@inserm.fr

Résumé du projet
Small GTPases of the RHO family, their regulators and their effectors assemble molecular platforms at the surface of membranes that control multiple signaling pathways. These signaling platforms are involved in various physiological functions and processes in the cell, such as the regulation of the cytoskeleton, adhesion, migration or the cell cycle. Mirroring these major functions, their deregulations can be at the origin of human pathologies such as immune deficiencies and inflammatory syndromes. However, how molecular defects in RHO pathways result in clinical symptoms is extremely complex and has remained poorly understood.
Using whole-exome sequencing, we and others previously identified patients with missense mutations affecting the small GTPase CDC42 that result in a spectrum of disabling skin diseases, often with inflammatory and immune symptoms. These rare diseases provide a unique opportunity to unravel the inner workings of RHO GTPases molecular circuits from the molecule to the patient. With this aim, we will use complementary techniques, including biochemistry, molecular and cell biology, flow cytometry and imaging. We will investigate the mutational landscape of the RHO pathways in a large and unique cohort of patients. In particular, we will determine to what extent new pathogenic mutations we have recently identified in the CDC42 gene, alter the subcellular localization of the corresponding protein. We will identify whether changes in the activation state of CDC42 are induced. We will study the biochemical and cellular defects associated with the mutations to determine the impact of the mutations on CDC42 function. We will particularly focus our studies to understand
how cytoskeletal elements (actin filaments and microtubules) can impact several inflammatory signaling pathways such as NF-kB, Pyrin and NLRP3 inflammasomes, and STING/type I IFNs.
The project should thus impact both fundamental and translational research in several ways.

Dernières Publications en lien avec le projet :
– El Masri R, Iannuzzo A, Kuentz P, Tacine R, Vincent M, Barbarot S, Morice-Picard F, Boralevi F, Oillarburu N, MazereeuwHautier J, Duffourd Y, Faivre L, Sorlin A, Vabres P, Delon J. A postzygotic GNA13 variant upregulates the RHOA/ROCK pathway and alters melanocyte function in a mosaic skin hypopigmentation syndrome. Nat Commun. 2025 Feb 18;16(1):1751. doi: 10.1038/s41467-025-56995-4. PMID: 39966435; PMCID: PMC11836271.
– Iannuzzo A, Delafontaine S, El Masri R, Tacine R, Prencipe G, Nishitani-Isa M, van Wijck RTA, Bhuyan F, de Jesus Rasheed AA, Coppola S, van Daele PLA, Insalaco A, Goldbach-Mansky R, Yasumi T, Tartaglia M, Meyts I, Delon J. Autoinflammatory patients with Golgi-trapped CDC42 exhibit intracellular trafficking defects leading to STING hyperactivation and ER stress. Nat Commun. 2024 Nov 16;15(1):9940. doi: 10.1038/s41467-024-54294-y. PMID: 39550374; PMCID: PMC11569173.
– Delafontaine S, Iannuzzo A, Bigley TM, Mylemans B, Rana R, Baatsen P, Poli MC, Rymen D, Jansen K, Mekahli D, Casteels I, Cassiman C, Demaerel P, Lepelley A, Frémond ML, Schrijvers R, Bossuyt X, Vints K, Huybrechts W, Tacine R, Willekens K, Corveleyn A, Boeckx B, Baggio M, Ehlers L, Munck S, Lambrechts D, Voet A, Moens L, Bucciol G, Cooper MA, Davis CM, *Delon J, *Meyts I. Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome. J Clin Invest. 2024 Jan 4;134(4):e163604. doi: 10.1172/JCI163604. PMID: 38175705; PMCID: PMC10866661. (*Equal contribution).
– El Masri R and Delon J. (2021). RHO GTPases: from new partners to complex immune syndromes. Nature Reviews Immunology. (8):499-513.
– Bekhouche B, Tourville A, Ravichandran Y, Tacine R, Abrami L, Dussiot M, Khau-Dancasius A, Boccara O, Khirat M, … van
der Goot FG, Cherfils J, Hermine O, Casanova JL, Bodemer C, Smahi A, Delon J. A toxic palmitoylation of Cdc42 enhances
NF-kB signaling and drives a severe autoinflammatory syndrome. Journal of Allergy and Clinical Immunology. 2020 Nov;146(5):1201-1204.e8.

Ce projet s’inscrit dans la perspective d’une thèse
si oui type de financement prévu : Concours de l’Ecole Doctorale
Ecole Doctorale de rattachement : BioSPC