| Autor: |
Owens DJ; INSERM UMRS_974, Centre for Research in Myology, Sorbonne Université, 75013 Paris, France.; Research Institute for Sport and Exercise Science, Liverpool John Moores University, Liverpool L3 3AF, UK., Fischer M; INSERM UMRS_974, Centre for Research in Myology, Sorbonne Université, 75013 Paris, France., Jabre S; INSERM UMRS_974, Centre for Research in Myology, Sorbonne Université, 75013 Paris, France., Moog S; Inovarion, 75013 Paris, France., Mamchaoui K; Association Institut de Myology, 75013 Paris, France., Butler-Browne G; INSERM UMRS_974, Centre for Research in Myology, Sorbonne Université, 75013 Paris, France., Coirault C; INSERM UMRS_974, Centre for Research in Myology, Sorbonne Université, 75013 Paris, France. |
| Abstrakt: |
Mutations in the LMNA gene, encoding the nuclear envelope A-type lamins, are responsible for muscular dystrophies, the most severe form being the LMNA -related congenital muscular dystrophy (L-CMD), with severe defects in myonucleus integrity. We previously reported that L-CMD mutations compromise the ability of muscle stem cells to modulate the yes-associated protein (YAP), a pivotal factor in mechanotransduction and myogenesis. Here, we investigated the intrinsic mechanisms by which lamins influence YAP subcellular distribution, by analyzing different conditions affecting the balance between nuclear import and export of YAP. In contrast to wild type (WT) cells, LMNA DK32 mutations failed to exclude YAP from the nucleus and to inactivate its transcriptional activity at high cell density, despite activation of the Hippo pathway. Inhibiting nuclear pore import abolished YAP nuclear accumulation in confluent mutant cells, thus showing persistent nuclear import of YAP at cell confluence. YAP deregulation was also present in congenital myopathy related to nesprin-1 KASH mutation, but not in cells expressing the LMNA H222P mutation, the adult form of lamin-related muscle dystrophy with reduced nuclear deformability. In conclusion, our data showed that L-CMD mutations increased YAP nuclear localization via an increased nuclear import and implicated YAP as a pathogenic contributor in muscle dystrophies caused by nuclear envelop defects. |
