Actin dynamics regulation by TTC7A/PI4KIIIα limits DNA damage and cell death under confinement - 04/10/23

Doi : 10.1016/j.jaci.2023.06.016

Tania Gajardo, PhD ^a,^b, Mathilde Bernard, MS ^c,^d,^{^{∗
These authors contributed equally to this work.}}, Marie Lô, MS ^a,^b,^{^{∗
These authors contributed equally to this work.}}, Elisa Turck, MS ^a,^b, Claire Leveau, PhD ^a,^b, Marie-Thérèse El-Daher, PhD ^a,^b, Alexandre Deslys, MS ^e, Patricia Panikulam, MS ^a,^b, Constantin Menche, MS ^f,^g, Mathieu Kurowska, MS ^a,^b, Gregoire Le Lay, MS ^c,^d, Lucie Barbier, PhD ^c,^d, Despina Moshous, MD, PhD ^b,^h, Bénédicte Neven, MD, PhD ^b,^h, Henner F. Farin, PhD ^f,^g, Alain Fischer, MD, PhD ^b,^h,ⁱ, Gaël Ménasché, PhD ^a,^b, Geneviève de Saint Basile, MD, PhD ^a,^b,^j, Pablo Vargas, PhD ^c,^d,^e,^⁎ , Fernando E. Sepulveda, PhD ^a,^b,^k,^⁎
^a 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
^b Imagine Institute, Université de Paris Cité, Paris, France
^c UMR 144, Institut Curie, Paris, France
^d Institut Pierre-Gilles de Gennes, Paris Sciences and Letters Research University, Paris, France
^e Leukomotion Lab, Université de Paris Cité, CNRS, INSERM, Institut Necker-Enfants Malades, F-75015 Paris, France
^f Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Main, Germany
^g Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt, Germany
^h Pediatric Immunology Hematology and Rheumatology Department, Université Paris Cité, Paris, France
ⁱ Collège de France, Paris, France
^j Centre d'Etude des Déficits Immunitaires, Necker-Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, Université Paris Cité, Paris, France
^k CNRS, Paris, France

^∗Corresponding authors: Fernando E. Sepulveda, PhD, INSERM U1163, Imagine Institute, 24 Boulevard de Montparnasse, F-75015 Paris, France.INSERM U1163Imagine Institute24 Boulevard de MontparnasseParisF-75015France^∗Pablo Vargas, PhD, Group leader Leukomotion Lab, INSERM U1151, 160 Rue de Vaugirard, F-75015, Paris, France.Group leader Leukomotion Lab, INSERM U1151160 Rue de VaugirardParisF-75015France

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Abstract

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.

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Key words : TTC7A, cell migration, actin dynamics, nuclear deformation, cell survival under confinement

Abbreviations used : 3D, ARP2/3, B-LCL, ctrl, DC, fsn, HD, iDC, mDC, mDia1, pAKT, PI3K, PI4KIIIα, PI4P

Plan

Ttc7 regulates 1D migration of immature murine dendritic cells

TTC7A controls human T-cell migration

Increased cell speed observed in TTC7A-deficient cells is mediated by reduced PI4KIIIα activity

Impairment of PI4KIIIα/DIAPH1/actin function in TTC7A-deficient cells disrupts the capacity to migrate through micrometric pores and irregularly confined microenvironments

TTC7A is essential for preservation of genome integrity and cell survival when migrating in complex 3D microenvironments

Discussion

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Vol 152 - N° 4

P. 949-960 - octobre 2023 Retour au numéro

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Actin dynamics regulation by TTC7A/PI4KIIIα limits DNA damage and cell death under confinement - 04/10/23

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