<p class="first" id="d5563599e233">YAP is a mechanosensitive transcriptional activator
with a critical role in cancer,
regeneration, and organ size control. Here, we show that force applied to the nucleus
directly drives YAP nuclear translocation by decreasing the mechanical restriction
of nuclear pores to molecular transport. Exposure to a stiff environment leads cells
to establish a mechanical connection between the nucleus and the cytoskeleton, allowing
forces exerted through focal adhesions to reach the nucleus. Force transmission then
leads to nuclear flattening, which stretches nuclear pores, reduces their mechanical
resistance to molecular transport, and increases YAP nuclear import. The restriction
to transport is further regulated by the mechanical stability of the transported protein,
which determines both active nuclear transport of YAP and passive transport of small
proteins. Our results unveil a mechanosensing mechanism mediated directly by nuclear
pores, demonstrated for YAP but with potential general applicability in transcriptional
regulation.
</p>