Myopathy associated LDB3 mutation causes Z-disc disassembly and protein aggregation through PKCα and TSC2-mTOR downregulation.
Commun Biol
; 4(1): 355, 2021 03 19.
Article
en En
| MEDLINE
| ID: mdl-33742095
ABSTRACT
Mechanical stress induced by contractions constantly threatens the integrity of muscle Z-disc, a crucial force-bearing structure in striated muscle. The PDZ-LIM proteins have been proposed to function as adaptors in transducing mechanical signals to preserve the Z-disc structure, however the underlying mechanisms remain poorly understood. Here, we show that LDB3, a well-characterized striated muscle PDZ-LIM protein, modulates mechanical stress signaling through interactions with the mechanosensing domain in filamin C, its chaperone HSPA8, and PKCα in the Z-disc of skeletal muscle. Studies of Ldb3Ala165Val/+ mice indicate that the myopathy-associated LDB3 p.Ala165Val mutation triggers early aggregation of filamin C and its chaperones at muscle Z-disc before aggregation of the mutant protein. The mutation causes protein aggregation and eventually Z-disc myofibrillar disruption by impairing PKCα and TSC2-mTOR, two important signaling pathways regulating protein stability and disposal of damaged cytoskeletal components at a major mechanosensor hub in the Z-disc of skeletal muscle.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Mutación Puntual
/
Músculo Esquelético
/
Miopatías Estructurales Congénitas
/
Mecanotransducción Celular
/
Proteínas Adaptadoras Transductoras de Señales
/
Proteína Quinasa C-alfa
/
Serina-Treonina Quinasas TOR
/
Proteínas con Dominio LIM
Tipo de estudio:
Etiology_studies
/
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
Commun Biol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos