| First Author | Pathak P | Year | 2021 |
| Journal | Commun Biol | Volume | 4 |
| Issue | 1 | Pages | 355 |
| PubMed ID | 33742095 | Mgi Jnum | J:305082 |
| Mgi Id | MGI:6704944 | Doi | 10.1038/s42003-021-01864-1 |
| Citation | Pathak P, et al. (2021) Myopathy associated LDB3 mutation causes Z-disc disassembly and protein aggregation through PKCalpha and TSC2-mTOR downregulation. Commun Biol 4(1):355 |
| abstractText | 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 PKCalpha in the Z-disc of skeletal muscle. Studies of Ldb3(Ala165Val/+) 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 PKCalpha 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. |
