Increased extracellular matrix stiffness regulates myofibroblast transformation through induction of autophagy-mediated Kindlin-2 cytoplasmic translocation.
Exp Cell Res
; 436(2): 113974, 2024 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-38346630
ABSTRACT
The extracellular matrix (ECM) mechanical properties regulate biological processes, such as fibroblast-myofibroblast transformation (FMT), which is a crucial component in pelvic organ prolapse (POP) development. The 'Kindlin-2' protein, expressed by fibroblasts, plays an important role in the development of the mesoderm, which is responsible for connective tissue formation; however, the role of Kindlin-2 in FMT remains to be explored. In this study, we aimed to explore the role of Kindlin-2 in FMT as it relates to POP. We found that ECM stiffness induces autophagy to translocate Kindlin-2 to the cytoplasm of L929 cells, where it interacts with and degrades MOB1, thereby facilitating Yes-associated protein (YAP) entry into the nucleus and influencing FMT progression. Stiffness-induced autophagy was inhibited when using an autophagy inhibitor, which blocked the translocation of Kindlin-2 to the cytoplasm and partially reversed high-stiffness-induced FMT. In patients with POP, we observed an increase in cytoplasmic Kindlin-2 and nuclear YAP levels. Similar changes in vaginal wall-associated proteins were observed in a mouse model of acute vaginal injury. In conclusion, Kindlin-2 is a key gene affecting ECM stiffness, which regulates FMT by inducing autophagy and may influence the development of POP.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas do Citoesqueleto
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Matriz Extracelular
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Miofibroblastos
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Proteínas Musculares
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article