Actin dynamics regulation by TTC7A/PI4KIIIα limits DNA damage and cell death under confinement.

Autor:	Gajardo T; Molecular Basis of Altered Immune Homeostasis Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite Mixte de Recherche (UMR) 1163, Paris, France; Imagine Institute, Université de Paris Cité, Paris, France., Bernard M; UMR 144, Institut Curie, Paris, France; Institut Pierre-Gilles de Gennes, Paris Sciences and Letters Research University, Paris, France., Lô M; Molecular Basis of Altered Immune Homeostasis Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite Mixte de Recherche (UMR) 1163, Paris, France; Imagine Institute, Université de Paris Cité, Paris, France., Turck E; Molecular Basis of Altered Immune Homeostasis Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite Mixte de Recherche (UMR) 1163, Paris, France; Imagine Institute, Université de Paris Cité, Paris, France., Leveau C; Molecular Basis of Altered Immune Homeostasis Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite Mixte de Recherche (UMR) 1163, Paris, France; Imagine Institute, Université de Paris Cité, Paris, France., El-Daher MT; Molecular Basis of Altered Immune Homeostasis Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite Mixte de Recherche (UMR) 1163, Paris, France; Imagine Institute, Université de Paris Cité, Paris, France., Deslys A; Leukomotion Lab, Université de Paris Cité, CNRS, INSERM, Institut Necker-Enfants Malades, F-75015 Paris, France., Panikulam P; Molecular Basis of Altered Immune Homeostasis Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite Mixte de Recherche (UMR) 1163, Paris, France; Imagine Institute, Université de Paris Cité, Paris, France., Menche C; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Main, Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt, Germany., Kurowska M; Molecular Basis of Altered Immune Homeostasis Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite Mixte de Recherche (UMR) 1163, Paris, France; Imagine Institute, Université de Paris Cité, Paris, France., Le Lay G; UMR 144, Institut Curie, Paris, France; Institut Pierre-Gilles de Gennes, Paris Sciences and Letters Research University, Paris, France., Barbier L; UMR 144, Institut Curie, Paris, France; Institut Pierre-Gilles de Gennes, Paris Sciences and Letters Research University, Paris, France., Moshous D; Imagine Institute, Université de Paris Cité, Paris, France; Pediatric Immunology Hematology and Rheumatology Department, Université Paris Cité, Paris, France., Neven B; Imagine Institute, Université de Paris Cité, Paris, France; Pediatric Immunology Hematology and Rheumatology Department, Université Paris Cité, Paris, France., Farin HF; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Main, Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt, Germany., Fischer A; Imagine Institute, Université de Paris Cité, Paris, France; Pediatric Immunology Hematology and Rheumatology Department, Université Paris Cité, Paris, France; Collège de France, Paris, France., Ménasché G; Molecular Basis of Altered Immune Homeostasis Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite Mixte de Recherche (UMR) 1163, Paris, France; Imagine Institute, Université de Paris Cité, Paris, France., de Saint Basile G; Molecular Basis of Altered Immune Homeostasis Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite Mixte de Recherche (UMR) 1163, Paris, France; Imagine Institute, Université de Paris Cité, Paris, France; Centre d'Etude des Déficits Immunitaires, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France., Vargas P; UMR 144, Institut Curie, Paris, France; Institut Pierre-Gilles de Gennes, Paris Sciences and Letters Research University, Paris, France; Leukomotion Lab, Université de Paris Cité, CNRS, INSERM, Institut Necker-Enfants Malades, F-75015 Paris, France. Electronic address: pablo.vargas@inserm.fr., Sepulveda FE; Molecular Basis of Altered Immune Homeostasis Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite Mixte de Recherche (UMR) 1163, Paris, France; Imagine Institute, Université de Paris Cité, Paris, France; CNRS, Paris, France. Electronic address: fernando.sepulveda@inserm.fr.
Jazyk:	angličtina
Zdroj:	The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2023 Oct; Vol. 152 (4), pp. 949-960. Date of Electronic Publication: 2023 Jun 29.
DOI:	10.1016/j.jaci.2023.06.016
Abstrakt:	Background: The actin cytoskeleton has a crucial role in the maintenance of the immune homeostasis by controlling various cellular processes, including cell migration. Mutations in TTC7A have been described as the cause of a primary immunodeficiency associated to different degrees of gut involvement and alterations in the actin cytoskeleton dynamics. Objectives: This study investigates the impact of TTC7A deficiency in immune homeostasis. In particular, the role of the TTC7A/phosphatidylinositol 4 kinase type III α pathway in the control of leukocyte migration and actin dynamics. Methods: Microfabricated devices were leveraged to study cell migration and actin dynamics of murine and patient-derived leukocytes under confinement at the single-cell level. Results: We show that TTC7A-deficient lymphocytes exhibit an altered cell migration and reduced capacity to deform through narrow gaps. Mechanistically, TTC7A-deficient phenotype resulted from impaired phosphoinositide signaling, leading to the downregulation of the phosphoinositide 3-kinase/AKT/RHOA regulatory axis and imbalanced actin cytoskeleton dynamics. TTC7A-associated phenotype resulted in impaired cell motility, accumulation of DNA damage, and increased cell death in dense 3-dimensional gels in the presence of chemokines. Conclusions: These results highlight a novel role of TTC7A as a critical regulator of lymphocyte migration. Impairment of this cellular function is likely to contribute to the pathophysiology underlying progressive immunodeficiency in patients. Competing Interests: Disclosure Statement This work was supported by the state funding from the Agence Nationale de la Recherche under “Investissements d’avenir” program (ANR-10-IAHU-01), and the French National Institute of Health and Medical Research (INSERM). T.G. was supported by the International PhD program of the Imagine Institute and the Fondation Bettencourt Schueller. M.B. was supported by Emergence Canceropole Ile-de-France (Syntec), ATEurope, and Institut Pierre-Gilles de Gennes High Risk/High Gain. M.L. was supported by the Imagine Institute (WP05T012). F.E.S. received funding and supports from The Agence Nationale de la Recherche (ANR-18-CE15-0017), the ARC Foundation (PJA 20191209614), La Ligue Contre le Cancer (RS19/75-79, RS20/75-30). G.M. received funding and support from La Ligue Contre le Cancer (RS21/75-3) and the ARC foundation (PJA 20181207755). P.V. received funding and support from the Agence Nationale de la Recherche (ANR-16-CE13-0009, ANR-21-CE17-0050, ANR-20-CE15-0019, Labex-IPGG ANR-10-IDEX-0001-02 PSL and ANR-10-LABX-31). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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