Mechanical force application to the nucleus regulates nucleocytoplasmic transport

Ion Andreu; Ignasi Granero-Moya; Nimesh R Chahare; Kessem Clein; Marc Molina-Jordán; Amy E M Beedle; Alberto Elosegui-Artola; Juan F Abenza; Leone Rossetti; Xavier Trepat; Barak Raveh; Pere Roca-Cusachs

doi:10.1038/s41556-022-00927-7

Mechanical force application to the nucleus regulates nucleocytoplasmic transport

Ion Andreu, Ignasi Granero-Moya, Nimesh R Chahare, Kessem Clein, Marc Molina-Jordán, Amy E M Beedle, Alberto Elosegui-Artola, Juan F Abenza, Leone Rossetti, Xavier Trepat, Barak Raveh, Pere Roca-Cusachs

Research output: Contribution to journal › Article › peer-review

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 for facilitated diffusion. Owing to this differential effect, force leads to the translocation of cargoes into or out of the nucleus 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, probably operating in parallel with others, with potential applicability across signalling pathways.

Original language	English
Pages (from-to)	896-905
Number of pages	10
Journal	Nature cell biology
Volume	24
Issue number	6
DOIs	https://doi.org/10.1038/s41556-022-00927-7
Publication status	Published - Jun 2022

Keywords

Active Transport, Cell Nucleus/physiology
Cell Nucleus/metabolism
Nuclear Pore/genetics
Protein Transport
Receptors, Cytoplasmic and Nuclear/metabolism

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10.1038/s41556-022-00927-7

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title = "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 for facilitated diffusion. Owing to this differential effect, force leads to the translocation of cargoes into or out of the nucleus 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, probably operating in parallel with others, with potential applicability across signalling pathways.",

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author = "Ion Andreu and Ignasi Granero-Moya and Chahare, {Nimesh R} and Kessem Clein and Marc Molina-Jord{\'a}n and Beedle, {Amy E M} and Alberto Elosegui-Artola and Abenza, {Juan F} and Leone Rossetti and Xavier Trepat and Barak Raveh and Pere Roca-Cusachs",

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year = "2022",

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doi = "10.1038/s41556-022-00927-7",

language = "English",

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T1 - Mechanical force application to the nucleus regulates nucleocytoplasmic transport

AU - Andreu, Ion

AU - Granero-Moya, Ignasi

AU - Chahare, Nimesh R

AU - Clein, Kessem

AU - Molina-Jordán, Marc

AU - Beedle, Amy E M

AU - Elosegui-Artola, Alberto

AU - Abenza, Juan F

AU - Rossetti, Leone

AU - Trepat, Xavier

AU - Raveh, Barak

AU - Roca-Cusachs, Pere

PY - 2022/6

Y1 - 2022/6

N2 - 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 for facilitated diffusion. Owing to this differential effect, force leads to the translocation of cargoes into or out of the nucleus 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, probably operating in parallel with others, with potential applicability across signalling pathways.

AB - 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 for facilitated diffusion. Owing to this differential effect, force leads to the translocation of cargoes into or out of the nucleus 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, probably operating in parallel with others, with potential applicability across signalling pathways.

KW - Active Transport, Cell Nucleus/physiology

KW - Cell Nucleus/metabolism

KW - Nuclear Pore/genetics

KW - Protein Transport

KW - Receptors, Cytoplasmic and Nuclear/metabolism

U2 - 10.1038/s41556-022-00927-7

DO - 10.1038/s41556-022-00927-7

M3 - Article

C2 - 35681009

SN - 1465-7392

VL - 24

SP - 896

EP - 905

JO - Nature cell biology

JF - Nature cell biology

IS - 6

ER -

Mechanical force application to the nucleus regulates nucleocytoplasmic transport

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Keywords

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