Actin dynamics regulation by TTC7A/PI4KIIIα limits DNA damage and cell death under confinement.
J Allergy Clin Immunol
; 152(4): 949-960, 2023 10.
Article
em En
| MEDLINE
| ID: mdl-37390900
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.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Actinas
/
Fosfatidilinositol 3-Quinases
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Allergy Clin Immunol
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
França