Mechanical force application to the nucleus regulates nucleocytoplasmic transport

Abstract

Mechanical force controls fundamental cellular processes in health and disease, and increasing evidence shows that the nucleus both experiences and senses applied forces. Such forces can lead to the nuclear translocation of proteins, but whether force controls nucleocytoplasmic transport, and how, remains unknown. Here we show that nuclear forces differentially control passive and facilitated nucleocytoplasmic transport, setting the rules for the mechanosensitivity of shuttling proteins. We demonstrate that nuclear force increases permeability across nuclear pore complexes, with a dependence on molecular weight that is stronger for passive than facilitated diffusion. Due to this differential effect, force leads to the translocation into or out of the nucleus of cargoes within a given range of molecular weight and affinity for nuclear transport receptors. Further, we show that the mechanosensitivity of several transcriptional regulators can be both explained by this mechanism, and engineered exogenously by introducing appropriate nuclear localization signals. Our work unveils a mechanism of mechanically induced signalling, likely operating in parallel to others, with potential applicability across signalling pathways.

Mechano-epigenetic regulation of extracellular matrix homeostasis via Yap and Taz

“…In tensile loading scenarios, mechanical cues are relayed through the contractile cytoskeleton to the nucleus to control transcriptional activities either indirectly through activation of other mechano-signaling pathways (e.g., stretch activated channels, mechano-responsive transcriptional co-activators such as YAP/TAZ) or directly (e.g. deformation of the nucleus, nuclear pores, and chromatin) (12)(13)(14)(15)(16). Whether through direct chromatin deformation or via mobilization of mechano-active factors, mechano-signaling pathways ultimately converge onto transcriptional regulators, which possess epigenetic and transcriptional activity to regulate cell function (17).…”

Understanding the role of mechanics in nucleocytoplasmic transport

“… 27 Relatedly and also using GFP as a marker, recent work has reported decreased diffusion across NPCs for cells under cellular energy depletion conditions, a treatment likely to reduce cell contractility and thereby force application to the nucleus. 28 Recently, using GFP-tagged artificial proteins of various MW, we have confirmed that diffusion through NPCs is faster under force 29 ( Fig. 1 ).…”

“…To explore this hypothesis, we recently combined artificial proteins of various MW with NLS sequences with different affinities for importin α. 29 These proteins did not have binding partners in either cytoplasm or nucleus or any regulation of their NLS sequence, and thereby directly probed the response of the nucleocytoplasmic transport cycle. These results showed that when forces reach the nucleus, facilitated diffusion through the NPC increased.…”

The role of cellular traction forces in deciphering nuclear mechanics

“…The transfer of mechanical forces from the extracellular matrix (ECM) to the cell not only affects the nuclear shape and cytoskeletal reorganization but also gene expression and remodeling of nuclear chromatins [1][2][3][4][5][6]. During cellular mechanosensation, cells respond to mechanical stimuli in their environment that in turn regulates important processes in normal as well as diseased states [7][8][9][10]. Cells in the body are subjected to different mechanical stresses, such as compression (in the bones and other tissues), shear stress (by blood flow), and tensile stresses (due to muscle stretching), and can be interpreted in the context of mechanobiology [11][12][13][14].…”