Tsc1 regulates tight junction independent of mTORC1.
Proc Natl Acad Sci U S A
; 118(30)2021 07 27.
Article
en En
| MEDLINE
| ID: mdl-34301883
ABSTRACT
Tuberous sclerosis complex 1 (Tsc1) is a tumor suppressor that functions together with Tsc2 to negatively regulate the mechanistic target of rapamycin complex 1 (mTORC1) activity. Here, we show that Tsc1 has a critical role in the tight junction (TJ) formation of epithelium, independent of its role in Tsc2 and mTORC1 regulation. When an epithelial cell establishes contact with neighboring cells, Tsc1, but not Tsc2, migrates from the cytoplasm to junctional membranes, in which it binds myosin 6 to anchor the perijunctional actin cytoskeleton to ß-catenin and ZO-1. In its absence, perijunctional actin cytoskeleton fails to form. In mice, intestine-specific or inducible, whole-body Tsc1 ablation disrupts adherens junction/TJ structures in intestine or skin epithelia, respectively, causing Crohn's disease-like symptoms in the intestine or psoriasis-like phenotypes on the skin. In patients with Crohn's disease or psoriasis, junctional Tsc1 levels in epithelial tissues are markedly reduced, concomitant with the TJ structure impairment, suggesting that Tsc1 deficiency may underlie TJ-related diseases. These findings establish an essential role of Tsc1 in the formation of cell junctions and underpin its association with TJ-related human diseases.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Psoriasis
/
Citoesqueleto de Actina
/
Enfermedad de Crohn
/
Uniones Estrechas
/
Diana Mecanicista del Complejo 1 de la Rapamicina
/
Proteína 1 del Complejo de la Esclerosis Tuberosa
Tipo de estudio:
Observational_studies
/
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2021
Tipo del documento:
Article
País de afiliación:
China