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

^*Corresponding author for this work

Physics

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

66 Citations (Scopus)

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

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@article{017d7748f2f04255b95dbb43dd0d0254,

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.",

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",

note = "Funding Information: We thank S. Usieto for technical support, and G. Ceada, S. Conti, M. Gonz{\'a}lez, S. Garcia-Manyes, M. Rout and the members of the Roca-Cusachs and Trepat lab for useful feedback and discussions. We acknowledge funding from the Spanish Ministry of Science and Innovation (PGC2018-099645-B-I00 to X.T., BFU2016-79916-P and PID2019-110298GB-I00 to P.R.-C.), the European Commission (H2020-FETPROACT-01-2016-731957 to X.T. and P.R.-C.), the European Research Council (Adv-883739 to X.T.), the Generalitat de Catalunya (2017-SGR-1602 to X.T. and P.R.-C.), The prize {\textquoteleft}ICREA Academia{\textquoteright} for excellence in research to P.R.-C., Fundaci{\'o} la Marat{\'o} de TV3 (201936-30-31 to P.R.-C.) and {\textquoteleft}la Caixa{\textquoteright} Foundation (grant LCF/PR/HR20/52400004 to X.T. and P.R.-C. and fellowships LCF/BQ/DR19/11740009 to I.G.-M. and LCF/BQ/DR19/11740009 to M.M.J.). A.E.M.B. is recipient of a Sir Henry Wellcome fellowship (210887/Z/18/Z). The Institue for Bioengineering of Catalonia (IBEC) is a recipient of a Severo Ochoa Award of Excellence from MINCIN. Funding Information: We thank S. Usieto for technical support, and G. Ceada, S. Conti, M. Gonz{\'a}lez, S. Garcia-Manyes, M. Rout and the members of the Roca-Cusachs and Trepat lab for useful feedback and discussions. We acknowledge funding from the Spanish Ministry of Science and Innovation (PGC2018-099645-B-I00 to X.T., BFU2016-79916-P and PID2019-110298GB-I00 to P.R.-C.), the European Commission (H2020-FETPROACT-01-2016-731957 to X.T. and P.R.-C.), the European Research Council (Adv-883739 to X.T.), the Generalitat de Catalunya (2017-SGR-1602 to X.T. and P.R.-C.), The prize {\textquoteleft}ICREA Academia{\textquoteright} for excellence in research to P.R.-C., Fundaci{\'o} la Marat{\'o} de TV3 (201936-30-31 to P.R.-C.) and {\textquoteleft}la Caixa{\textquoteright} Foundation (grant LCF/PR/HR20/52400004 to X.T. and P.R.-C. and fellowships LCF/BQ/DR19/11740009 to I.G.-M. and LCF/BQ/DR19/11740009 to M.M.J.). A.E.M.B. is recipient of a Sir Henry Wellcome fellowship (210887/Z/18/Z). The Institue for Bioengineering of Catalonia (IBEC) is a recipient of a Severo Ochoa Award of Excellence from MINCIN. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = jun,

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

language = "English",

volume = "24",

pages = "896--905",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Research",

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TY - JOUR

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

N1 - Funding Information: We thank S. Usieto for technical support, and G. Ceada, S. Conti, M. González, S. Garcia-Manyes, M. Rout and the members of the Roca-Cusachs and Trepat lab for useful feedback and discussions. We acknowledge funding from the Spanish Ministry of Science and Innovation (PGC2018-099645-B-I00 to X.T., BFU2016-79916-P and PID2019-110298GB-I00 to P.R.-C.), the European Commission (H2020-FETPROACT-01-2016-731957 to X.T. and P.R.-C.), the European Research Council (Adv-883739 to X.T.), the Generalitat de Catalunya (2017-SGR-1602 to X.T. and P.R.-C.), The prize ‘ICREA Academia’ for excellence in research to P.R.-C., Fundació la Marató de TV3 (201936-30-31 to P.R.-C.) and ‘la Caixa’ Foundation (grant LCF/PR/HR20/52400004 to X.T. and P.R.-C. and fellowships LCF/BQ/DR19/11740009 to I.G.-M. and LCF/BQ/DR19/11740009 to M.M.J.). A.E.M.B. is recipient of a Sir Henry Wellcome fellowship (210887/Z/18/Z). The Institue for Bioengineering of Catalonia (IBEC) is a recipient of a Severo Ochoa Award of Excellence from MINCIN. Funding Information: We thank S. Usieto for technical support, and G. Ceada, S. Conti, M. González, S. Garcia-Manyes, M. Rout and the members of the Roca-Cusachs and Trepat lab for useful feedback and discussions. We acknowledge funding from the Spanish Ministry of Science and Innovation (PGC2018-099645-B-I00 to X.T., BFU2016-79916-P and PID2019-110298GB-I00 to P.R.-C.), the European Commission (H2020-FETPROACT-01-2016-731957 to X.T. and P.R.-C.), the European Research Council (Adv-883739 to X.T.), the Generalitat de Catalunya (2017-SGR-1602 to X.T. and P.R.-C.), The prize ‘ICREA Academia’ for excellence in research to P.R.-C., Fundació la Marató de TV3 (201936-30-31 to P.R.-C.) and ‘la Caixa’ Foundation (grant LCF/PR/HR20/52400004 to X.T. and P.R.-C. and fellowships LCF/BQ/DR19/11740009 to I.G.-M. and LCF/BQ/DR19/11740009 to M.M.J.). A.E.M.B. is recipient of a Sir Henry Wellcome fellowship (210887/Z/18/Z). The Institue for Bioengineering of Catalonia (IBEC) is a recipient of a Severo Ochoa Award of Excellence from MINCIN. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

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.

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DO - 10.1038/s41556-022-00927-7

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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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