A/C lamins, intermediate filament proteins encoded by the LMNA gene, are a key structural component of the nuclear envelope and contribute to the transmission of mechanical signals essential for cell proliferation and differentiation. Mutations in this gene cause laminopathies, a heterogeneous group of disorders that includes muscular dystrophies and cardiomyopathies. The most severe form, LMNA-related congenital muscular dystrophy (L-CMD), is associated with profound alterations of nuclear integrity in muscle cells. The mechanisms by which these mutations impair muscle function, however, remain poorly understood. Previous work by this team had shown that L-CMD mutations compromise the ability of muscle stem cells to modulate YAP (yes-associated protein), a central transcriptional cofactor of mechanotransduction and myogenesis, whose activity largely depends on its localization between the cytoplasm and the nucleus.
To understand how lamins influence the subcellular distribution of YAP, the researchers investigated the balance between nuclear import and export under various conditions, particularly at high cell density. Unlike healthy cells, cells carrying the LMNAΔK32 mutation failed to exclude YAP from the nucleus or to inactivate its transcriptional activity when cells reached confluence, despite activation of the Hippo pathway. Indeed, the mutant cells displayed high levels of YAP phosphorylated on serine 127 while retaining this protein in the nucleus, indicating that nuclear export was no longer sufficient to counterbalance entry. By blocking import with importazole, an inhibitor of importin β, the authors abolished nuclear accumulation of YAP in confluent mutant cells, demonstrating the persistence of active nuclear import at confluence. Functionally, confluent LMNAΔK32 cells overexpressed YAP and its target genes CTGF and MYL9, and showed increased TEAD-dependent transcriptional activity.
This dysregulation of YAP was also observed in a congenital myopathy associated with a mutation of nesprin-1 (nesprin-1ΔKASH), another nuclear envelope protein, but not in cells carrying the LMNAH222P mutation, which causes an adult-onset form of dystrophy with reduced nuclear deformability. The authors thus establish a correlation between YAP dysregulation, nuclear envelope defects, and disease severity, suggesting that nuclear deformations themselves promote YAP translocation through the nuclear pore complex. Given that retention of YAP in the nucleus favors the proliferation of myogenic precursors at the expense of their differentiation, this work identifies YAP as a potential pathogenic contributor to muscular dystrophies linked to nuclear envelope defects. Further studies are still needed to clarify its exact contribution to the pathophysiology of these dystrophies.