How Mechanical Forces at the Nuclear Envelope Regulate Yki/YAP Localization.

Mechanical cues regulate Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) not only through upstream Hippo kinases but also by controlling nuclear envelope properties. Forces transmitted from the cytoskeleton to the nucleus through linkers of nucleoskeleton and cytoskeleton (LINC) complexes and the lamina tune nuclear stiffness and deformation thresholds, while nuclear pore complexes act as mechanogated transport channels that can favor YAP nuclear localization under load. In parallel, inner nuclear membrane (INM) proteins and the lamina organize chromatin-lamina contacts that set transcriptional competence once YAP enters the nucleus. Emerging work further implicates additional INM components, including NEMP1 and LEM-domain proteins (e.g., Emerin, LAP2β), in coupling nuclear mechanics, transport, and chromatin organization to YAP output. Together, these modules integrate force transmission, transport, and chromatin organization to determine the magnitude and selectivity of YAP-dependent transcription under mechanical stress.