Mechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP

García-García, María; Sánchez-Perales, Sara; Jarabo, Patricia; Huyton, Trevor; Fu, Liran; Ng, Sheung Chun; Sotodosos-Alonso, Laura; Vázquez, Jesús; Casas‐Tintó, Sergio; Görlich, Dirk; Echarri, Asier; Pozo, Miguel Á. del

doi:10.1038/s41467-022-28693-y

Cited by 45 publications

(41 citation statements)

References 143 publications

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“…On top of this mechanism, indirect effects mediated for instance by changes in importin α levels (Extended Data fig. 3) or by competition between cargoes for importin binding (as recently demonstrated between YAP and importin 7 65 ) may play a role in different contexts.…”

Section: Discussionmentioning

confidence: 93%

Mechanical force application to the nucleus regulates nucleocytoplasmic transport

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 93%

Mechanical force application to the nucleus regulates nucleocytoplasmic transport

et al. 2022

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“…For example, both dnKASH 33 expression and Sun1/2 co-depletion 34 decrease nuclear β-Catenin levels. In the case of Yap, dnKASH expression 35 and depletion of Nesprin1 36 both inhibit nuclear translocation through nuclear pore complexes in response to mechanical stimulus, potentially by limiting cytoskeleton-induced nuclear deformations, or by impairing association with Yap's nuclear transporter, Importin 7 37 . LINC-mediated cytoskeletal connections also affect deformations of the inner nuclear membrane: for example, it dnKASH expression reduces stretching of LaminA/C measured via FRET-based LaminA/C force sensor 38 , and decreases the chromatin deformations during cardiomyocyte contractions 39 .…”

Section: Introductionmentioning

confidence: 99%

Depletion of Sun1/2 induces heterochromatin accrual in mesenchymal stem cells during adipogenesis

Goelzer

Howard

Zavala

et al. 2022

Preprint

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Mechanical signals regulate adipogenic differentiation of mesenchymal stem cells (MSCs). Critical to the mechano-regulation of MSCs, Linker of the Nucleoskeleton and Cytoskeleton (LINC) complexes are integral to both nucleo-cytoskeletal signal transduction and structural integrity of the nucleus. The LINC complex is made of Nesprin proteins that associate with the cytoskeleton on the outer nuclear membrane (ONM) and Sun proteins that bound to nuclear lamina and chromatin at the inner nuclear membrane (INM). In addition to their role in the LINC complex function, depletion of Sun1/2 effects chromosomal tethering to the nuclear envelope, nuclear morphology, and chromatin organization. Suggesting that Sun1/2 proteins may regulate chromatin organization and adipogenic differentiation independent of the LINC complex mediated nucleo-cytoskeletal connectivity. To test this hypothesis Sun1/2 depletion was compared to expression of a dominant-negative KASH (dnKASH) domain to decouple nucleus from cytoskeleton by inhibiting Nesprin-SUN association. Sun1/2 depletion inhibited fat droplet formation and production of adipogenic proteins such as Adipoq, which were supported by RNA-seq showing decreased adipogensis. In contrast dnKASH responded oppositely, increasing fat droplet formation, Adipoq and adipogenic gene expression. At the chromatin level, Sun1/2 depletion increased H3K9me3 levels, increased H3K9me3 foci count, and enrichment on Adipoq. No increase of H3K9me3 levels, foci count, or increased H3K9me3 enrichment on Adipoq was found during dnKASH expression. We conclude that physically decoupling of the LINC complex via dnKASH accelerates adipogenesis and that depletion of Sun1/2 increases heterochromatin accrual and inhibits adipogenesis independent of the LINC complex function.

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“…An increasing number of proteins are identified to contain the monopartite classical importin α NLS sequences, KRRR and KRKXK ( 50 – 57 ). Recently, using a bio-informatics approach, based on bibliographic and simulation data, and experimental in vitro validation, we have presented the sequence EKRKI(E/R)(K/L/R/S/T) as a recognition motif for binding with Importin 7 ( 58 ), a result recently confirmed by another group ( 59 ) while recent data [( 60 ) under review] identified the sequences LPPRS(G/P)P and KP(K/Y)LV as recognition motifs for importins 4 and 5 binding, respectively.…”

Section: Introductionmentioning

confidence: 78%

Importins involved in the nuclear transportation of steroid hormone receptors: In silico and in vitro data

et al. 2022

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The nuclear receptor superfamily (NRS) consists of 48 receptors for lipophilic substances and is divided into 7 different subfamilies, with subfamily 3 comprising steroid hormone receptors. Several nuclear receptors usually bind their cognate ligands in the cytosol and the complex (mono- or dimerized) is transported to the nucleus, where it acts as a transcription initiating factor for a number of genes. The general structure of nuclear receptors consists of an N-terminal activating domain (A/B), important for the binding of activating or inhibitory co-factors, the DNA-binding domain (C), responsible for the association of the receptor-ligand-co-factor complex to the nucleus, the ligand-AF2 domain (E/F), where ligand binding occurs as well as that of ligand-dependent activating/inhibiting factors, and a flexible/non-structured domain (D), linking the DBD and LBD, called hinge region, on which a significant number of post-translational modifications occur. This hinge domain, for the sub-class of steroid receptors, is a non-structured domain and was reported as mainly responsible for the nuclear transport of steroid receptors, since it contains a specific amino acid sequence (Nuclear Localization Signal-NLS), recognized by importin α. In addition to the importin α/β complex, a number of other importins have been discovered and reported to be responsible for the nuclear transport of a number of significant proteins; however, the corresponding recognition sequences for these importins have not been identified. Recently, we have reported the identification of the NLS sequences for importins 4, 5 and 7. In this work, we provide in silico data, followed by experimental in vitro validation, showing that these alternative importins are responsible for the nuclear transportation of steroid hormone receptors such as ERα, AR and PR, and therefore they may consist of alternative targets for the pharmacological manipulation of steroid hormone actions. Moreover, we provide additional in silico data for the hinge region of steroid hormone receptors which is highly enriched with NLS sequences for importins 4, 5 and 7, in addition to the recognition NLS for importin α/β.

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Mechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP

Cited by 45 publications

References 143 publications

Mechanical force application to the nucleus regulates nucleocytoplasmic transport

Mechanical force application to the nucleus regulates nucleocytoplasmic transport

Depletion of Sun1/2 induces heterochromatin accrual in mesenchymal stem cells during adipogenesis

Importins involved in the nuclear transportation of steroid hormone receptors: In silico and in vitro data

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