Publications

Mechanotransduction mediated by the tension in lipid membranes is a well-established paradigm. This has been studied largely in the context of the plasma membrane, but recent work shows that it applies also to endomembranes, and specifically to the nuclear envelope. Here, we review membrane tension-mediated mechanotransduction at the nuclear envelope by focusing on its two best characterized modes of action: the cytosolic phospholipase A2 (cPLA2) pathway, and nuclear pore dilation. We discuss the mechanisms involved and their physiological implications. Finally, we discuss how nuclear envelope tension can be controlled and measured, and how its properties enable mechanosensing with different context-dependency than that of the plasma membrane. These properties apply to cPLA2 and nuclear pore complexes but potentially also to many other mechanosensors yet to be discovered.

JTD Keywords: Arachidonic-acid release, Bone-formation, C2 domain, Cytosolic phospholipase a(2), Cytosolic phospholipase a2, Force, Lipid-binding domain, Mechanobiology, Membrane, Membrane tension, Monolayer surface pressure, Nuclear deformation, Nuclear envelope, Nuclear pore complex, Nuclear transport, Nucleus, Packing, Pore complex, Tension, Yap

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. Force-dependent changes in nuclear pores control protein access to the nucleus.

JTD Keywords: Atomic force microscopy, Hippo pathway, Mechanosensing, Mechanotransduction, Molecular mechanical stability, Nuclear mechanics, Nuclear pores, Nuclear transport, Rigidity sensing, Transcription regulation