Fibrillar adhesion dynamics govern the timescales of nuclear mechano-response via the vimentin cytoskeleton
Source abstract
Abstract
Abstract The cell nucleus is continuously exposed to external signals, of both chemical and mechanical nature. To ensure proper cellular response, cells need to regulate the transmission, timing and duration of these signals. Although such timescale regulation is well described for chemical signals, whether and how it applies to mechanical signals reaching the nucleus is still not fully understood. Here we demonstrate that the formation of fibrillar adhesions locks the nucleus in a mechanically deformed conformation, setting the mechano-response timescale to that of fibrillar adhesion remodelling (~1 h). This process encompasses both mechanical deformation and associated mechanotransduction (such as via YAP), in response to both increased and decreased mechanical stimulation. The underlying mechanism is the anchoring of the vimentin cytoskeleton to fibrillar adhesions and the extracellular matrix through plectin 1f, which maintains nuclear deformation. Our results reveal a mechanism to regulate the timescale of mechanical adaptation, effectively setting a low-pass filter to mechanotransduction.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Cellular Mechanics and Interactions · Skin and Cellular Biology Research · Nuclear Structure and Function
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (86)
Show source-provided references
1. Jaalouk, D. E. & Lammerding, J. Mechanotransduction gone awry. Nat. Rev. Mol. Cell Biol. 10, 63–73 (2009).10.1038/nrm2597 ↗
2. Chin, L., Xia, Y., Discher, D. E. & Janmey, P. A. Mechanotransduction in cancer. Curr. Opin. Chem. Eng. 11, 77–84 (2016).10.1016/j.coche.2016.01.011 ↗
3. Elosegui-Artola, A. et al. Force triggers YAP nuclear entry by regulating transport across nuclear pores. Cell 171, 1397–1410.e14 (2017).10.1016/j.cell.2017.10.008 ↗
4. Seelbinder, B. et al. Nuclear deformation guides chromatin reorganization in cardiac development and disease. Nat. Biomed. Eng. 5, 1500–1516 (2021).10.1038/s41551-021-00823-9 ↗
5. Damodaran, K. et al. Compressive force induces reversible chromatin condensation and cell geometry–dependent transcriptional response. Mol. Biol. Cell 29, 3039–3051 (2018).10.1091/mbc.E18-04-0256 ↗
6. Venturini, V. et al. The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior. Science 370, eaba2644 (2020).10.1126/science.aba2644 ↗
7. Lomakin, A. J. et al. The nucleus acts as a ruler tailoring cell responses to spatial constraints. Science 370, eaba2894 (2020).10.1126/science.aba2894 ↗
8. Andreu, I. et al. Mechanical force application to the nucleus regulates nucleocytoplasmic transport. Nat. Cell Biol. 24, 896–905 (2022).10.1038/s41556-022-00927-7 ↗
9. Andreu, I. et al. The force loading rate drives cell mechanosensing through both reinforcement and cytoskeletal softening. Nat. Commun. 12, 4229 (2021).10.1038/s41467-021-24383-3 ↗
10. Strohmeyer, N., Bharadwaj, M., Costell, M., Fässler, R. & Müller, D. J. Fibronectin-bound α5β1 integrins sense load and signal to reinforce adhesion in less than a second. Nat. Mater. 16, 1262–1270 (2017).10.1038/nmat5023 ↗
11. Webb, D. J. et al. FAK–Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly. Nat. Cell Biol. 6, 154–161 (2004).10.1038/ncb1094 ↗
12. Nava, M. M. et al. Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage. Cell 181, 800–817.e22 (2020).10.1016/j.cell.2020.03.052 ↗
13. Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).10.1016/j.cell.2009.10.027 ↗
14. Laklai, H. et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 22, 497–505 (2016).10.1038/nm.4082 ↗
15. Li, C. X. et al. MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells. Nat. Mater. 16, 379–389 (2017).10.1038/nmat4780 ↗
16. Walker, C. J. et al. Nuclear mechanosensing drives chromatin remodelling in persistently activated fibroblasts. Nat. Biomed. Eng. 5, 1485–1499 (2021).10.1038/s41551-021-00709-w ↗
17. Yang, C., Tibbitt, M. W., Basta, L. & Anseth, K. S. Mechanical memory and dosing influence stem cell fate. Nat. Mater. 13, 645–652 (2014).10.1038/nmat3889 ↗
18. Killaars, A. R. et al. Extended exposure to stiff microenvironments leads to persistent chromatin remodeling in human mesenchymal stem cells. Adv. Sci. 6, 1801483 (2019).10.1002/advs.201801483 ↗
19. Price, C. C., Mathur, J., Boerckel, J. D., Pathak, A. & Shenoy, V. B. Dynamic self-reinforcement of gene expression determines acquisition of cellular mechanical memory. Biophys. J. 120, 5074–5089 (2021).10.1016/j.bpj.2021.10.006 ↗
20. Iyer, K. V., Pulford, S., Mogilner, A. & Shivashankar, G. V. Mechanical activation of cells induces chromatin remodeling preceding MKL nuclear transport. Biophys. J. 103, 1416–1428 (2012).10.1016/j.bpj.2012.08.041 ↗
21. Chu, F.-Y., Haley, S. C. & Zidovska, A. On the origin of shape fluctuations of the cell nucleus. Proc. Natl Acad. Sci. USA 114, 10338–10343 (2017).10.1073/pnas.1702226114 ↗
22. Almonacid, M. et al. Active fluctuations of the nuclear envelope shape the transcriptional dynamics in oocytes. Dev. Cell 51, 145–157.e10 (2019).10.1016/j.devcel.2019.09.010 ↗
23. Makhija, E., Jokhun, D. S. & Shivashankar, G. V. Nuclear deformability and telomere dynamics are regulated by cell geometric constraints. Proc. Natl Acad. Sci. USA 113, E32–E40 (2016).10.1073/pnas.1513189113 ↗
24. Jackson, J. A. et al. Scaling behaviour and control of nuclear wrinkling. Nat. Phys. 19, 1927–1935 (2023).10.1038/s41567-023-02216-y ↗
25. Doncic, A. et al. Compartmentalization of a bistable switch enables memory to cross a feedback-driven transition. Cell 160, 1182–1195 (2015).10.1016/j.cell.2015.02.032 ↗
26. Wang, L. et al. Bistable switches control memory and plasticity in cellular differentiation. Proc. Natl Acad. Sci. USA 106, 6638–6643 (2009).10.1073/pnas.0806137106 ↗
27. Xiong, W. & Ferrell, J. E. A positive-feedback-based bistable ‘memory module’ that governs a cell fate decision. Nature 426, 460–465 (2003).10.1038/nature02089 ↗
28. Burrill, D. R. & Silver, P. A. Making cellular memories. Cell 140, 13–18 (2010).10.1016/j.cell.2009.12.034 ↗
29. d’Alessandro, J. et al. Cell migration guided by long-lived spatial memory. Nat. Commun. 12, 4118 (2021).10.1038/s41467-021-24249-8 ↗
30. Almeida, J. A., Mathur, J., Lee, Y. L., Sarker, B. & Pathak, A. Mechanically primed cells transfer memory to fibrous matrices for invasion across environments of distinct stiffness and dimensionality. Mol. Biol. Cell 34, ar54 (2023).10.1091/mbc.E22-10-0469 ↗
31. Carraher, C. L. & Schwarzbauer, J. E. Regulation of matrix assembly through rigidity-dependent fibronectin conformational changes. J. Biol. Chem. 288, 14805–14814 (2013).10.1074/jbc.M112.435271 ↗
32. Barber-Pérez, N. et al. Mechano-responsiveness of fibrillar adhesions on stiffness-gradient gels. J. Cell Sci. 133, jcs242909 (2020).10.1242/jcs.242909 ↗
33. Clark, K. et al. A specific α5β1-integrin conformation promotes directional integrin translocation and fibronectin matrix formation. J. Cell Sci. 118, 291–300 (2005).10.1242/jcs.01623 ↗
34. Wei, S. C. et al. Matrix stiffness drives epithelial–mesenchymal transition and tumour metastasis through a TWIST1–G3BP2 mechanotransduction pathway. Nat. Cell Biol. 17, 678–688 (2015).10.1038/ncb3157 ↗
35. Zhang, K. et al. Mechanical signals regulate and activate SNAIL1 protein to control the fibrogenic response of cancer-associated fibroblasts. J. Cell Sci. 129, 1989–2002 (2016).10.1242/jcs.180539 ↗
36. Yarmola, E. G., Somasundaram, T., Boring, T. A., Boring, I. & Bubb, M. R. Actin-latrunculin A structure and function: differential modulation of actin-binding protein function by latrunculin A. J. Biol. Chem. 275, 28120–28127 (2000).10.1074/jbc.M004253200 ↗
37. Carlier, M. F., Criquet, P., Pantaloni, D. & Korn, E. D. Interaction of cytochalasin D with actin filaments in the presence of ADP and ATP. J. Biol. Chem. 261, 2041–2050 (1986).10.1016/S0021-9258(17)35894-5 ↗
38. Iskratsch, T. et al. FHOD1 is needed for directed forces and adhesion maturation during cell spreading and migration. Dev. Cell 27, 545–559 (2013).10.1016/j.devcel.2013.11.003 ↗
39. Lehtimäki, J. I., Rajakylä, E. K., Tojkander, S. & Lappalainen, P. Generation of stress fibers through myosin-driven reorganization of the actin cortex. eLife 10, e60710 (2021).10.7554/eLife.60710 ↗
40. Nair, U. B. et al. Crystal structures of monomeric actin bound to cytochalasin D. J. Mol. Biol. 384, 848–864 (2008).10.1016/j.jmb.2008.09.082 ↗
41. Kovács, M., Tóth, J., Hetényi, C., Málnási-Csizmadia, A. & Sellers, J. R. Mechanism of blebbistatin inhibition of myosin II. J. Biol. Chem. 279, 35557–35563 (2004).10.1074/jbc.M405319200 ↗
42. Ishizaki, T. et al. Pharmacological properties of Y-27632, a specific inhibitor of Rho-associated kinases. Mol. Pharmacol. 57, 976–983 (2000).10.1016/S0026-895X(24)26508-1 ↗
43. Granero-Moya, I. et al. Nucleocytoplasmic transport senses mechanical forces independently of cell density in cell monolayers. J. Cell Sci. 137, jcs262363 (2024).10.1242/jcs.262363 ↗
44. Tomer, D. et al. A new mechanism of fibronectin fibril assembly revealed by live imaging and super-resolution microscopy. J. Cell Sci. 135, jcs260120 (2022).10.1242/jcs.260120 ↗
45. Ensenberger, M. G. et al. Specific interactions between F1 adhesin of Streptococcus pyogenes and N-terminal modules of fibronectin. J. Biol. Chem. 276, 35606–35613 (2001).10.1074/jbc.M105417200 ↗
46. Tomasini-Johansson, B. R. et al. A 49-residue peptide from adhesin F1 of Streptococcus pyogenes inhibits fibronectin matrix assembly. J. Biol. Chem. 276, 23430–23439 (2001).10.1074/jbc.M103467200 ↗
47. Missirlis, D., Haraszti, T., Kessler, H. & Spatz, J. P. Fibronectin promotes directional persistence in fibroblast migration through interactions with both its cell-binding and heparin-binding domains. Sci. Rep. 7, 3711 (2017).10.1038/s41598-017-03701-0 ↗
48. Pankov, R. et al. Integrin dynamics and matrix assembly: tensin-dependent translocation of α5β1 integrins promotes early fibronectin fibrillogenesis. J. Cell Biol. 148, 1075–1090 (2000).10.1083/jcb.148.5.1075 ↗
49. Patteson, A. E. et al. Vimentin protects cells against nuclear rupture and DNA damage during migration. J. Cell Biol. 218, 4079–4092 (2019).10.1083/jcb.201902046 ↗
50. Burgstaller, G., Gregor, M., Winter, L. & Wiche, G. Keeping the vimentin network under control: cell–matrix adhesion–associated plectin 1f affects cell shape and polarity of fibroblasts. Mol. Biol. Cell 21, 3362–3375 (2010).10.1091/mbc.e10-02-0094 ↗
51. Wilhelmsen, K. et al. Nesprin-3, a novel outer nuclear membrane protein, associates with the cytoskeletal linker protein plectin. J. Cell Biol. 171, 799–810 (2005).10.1083/jcb.200506083 ↗
52. Serra-Picamal, X. et al. Mechanical waves during tissue expansion. Nat. Phys. 8, 628–634 (2012).10.1038/nphys2355 ↗
53. Tambe, D. T. et al. Collective cell guidance by cooperative intercellular forces. Nat. Mater. 10, 469–475 (2011).10.1038/nmat3025 ↗
54. Srivastava, L. K., Ju, Z., Ghagre, A. & Ehrlicher, A. J. Spatial distribution of lamin A/C determines nuclear stiffness and stress-mediated deformation. J. Cell Sci. 134, jcs248559 (2021).10.1242/jcs.248559 ↗
55. Pogoda, K. et al. Unique role of vimentin networks in compression stiffening of cells and protection of nuclei from compressive stress. Nano Lett. 22, 4725–4732 (2022).10.1021/acs.nanolett.2c00736 ↗
56. Denais, C. M. et al. Nuclear envelope rupture and repair during cancer cell migration. Science 352, 353–358 (2016).10.1126/science.aad7297 ↗
57. Kloxin, A. M., Kasko, A. M., Salinas, C. N. & Anseth, K. S. Photodegradable hydrogels for dynamic tuning of physical and chemical properties. Science 324, 59–63 (2009).10.1126/science.1169494 ↗
58. Kechagia, Z. et al. The laminin–keratin link shields the nucleus from mechanical deformation and signalling. Nat. Mater. 22, 1409–1420 (2023).10.1038/s41563-023-01657-3 ↗
59. Laly, A. C. et al. The keratin network of intermediate filaments regulates keratinocyte rigidity sensing and nuclear mechanotransduction. Sci. Adv. 7, eabd6187 (2021).10.1126/sciadv.abd6187 ↗
60. Shah, P. et al. Nuclear deformation causes DNA damage by increasing replication stress. Curr. Biol. 31, 753–765.e6 (2021).10.1016/j.cub.2020.11.037 ↗
61. Oria, R. et al. Force loading explains spatial sensing of ligands by cells. Nature 552, 219–224 (2017).10.1038/nature24662 ↗
62. van Bodegraven, E. J. & Etienne-Manneville, S. Intermediate filaments from tissue integrity to single molecule mechanics. Cells 10, 1905 (2021).10.3390/cells10081905 ↗
63. Seltmann, K., Fritsch, A. W., Käs, J. A. & Magin, T. M. Keratins significantly contribute to cell stiffness and impact invasive behavior. Proc. Natl Acad. Sci. USA 110, 18507–18512 (2013).10.1073/pnas.1310493110 ↗
64. Infante, E. & Etienne-Manneville, S. Intermediate filaments: integration of cell mechanical properties during migration. Front. Cell Dev. Biol. 10, 951816 (2022).10.3389/fcell.2022.951816 ↗
65. Hu, J. et al. High stretchability, strength, and toughness of living cells enabled by hyperelastic vimentin intermediate filaments. Proc. Natl Acad. Sci. USA 116, 17175–17180 (2019).10.1073/pnas.1903890116 ↗
66. Wu, H. et al. Vimentin intermediate filaments and filamentous actin form unexpected interpenetrating networks that redefine the cell cortex. Proc. Natl Acad. Sci. USA 119, e2115217119 (2022).10.1073/pnas.2115217119 ↗
67. Alisafaei, F. et al. Vimentin is a key regulator of cell mechanosensing through opposite actions on actomyosin and microtubule networks. Commun. Biol. 7, 658 (2024).10.1038/s42003-024-06366-4 ↗
68. Charrier, E. E. & Janmey, P. A. in Methods in Enzymology (eds Omary, M. B. & Liem, R. K. H.) 35–57 (Academic Press, 2016).10.1016/bs.mie.2015.09.009 ↗
69. Snider, N. T. & Omary, M. B. Post-translational modifications of intermediate filament proteins: mechanisms and functions. Nat. Rev. Mol. Cell Biol. 15, 163–177 (2014).10.1038/nrm3753 ↗
70. Murray, M. E., Mendez, M. G. & Janmey, P. A. Substrate stiffness regulates solubility of cellular vimentin. Mol. Biol. Cell 25, 87–94 (2014).10.1091/mbc.e13-06-0326 ↗
71. Atherton, P. et al. Tensin3 interaction with talin drives the formation of fibronectin-associated fibrillar adhesions. J. Cell Biol. 221, e202107022 (2022).10.1083/jcb.202107022 ↗
72. Goreczny, G. J., Forsythe, I. J. & Turner, C. E. Hic-5 regulates fibrillar adhesion formation to control tumor extracellular matrix remodeling through interaction with tensin1. Oncogene 37, 1699–1713 (2018).10.1038/s41388-017-0074-2 ↗
73. Goreczny, G. J., Ouderkirk-Pecone, J. L., Olson, E. C., Krendel, M. & Turner, C. E. Hic-5 remodeling of the stromal matrix promotes breast tumor progression. Oncogene 36, 2693–2703 (2017).10.1038/onc.2016.422 ↗
74. Vohnoutka, R. B. et al. The focal adhesion scaffold protein Hic-5 regulates vimentin organization in fibroblasts. Mol. Biol. Cell 30, 3037–3056 (2019).10.1091/mbc.E19-08-0442 ↗
75. Rezniczek, G. A., Abrahamsberg, C., Fuchs, P., Spazierer, D. & Wiche, G. Plectin 5′-transcript diversity: short alternative sequences determine stability of gene products, initiation of translation and subcellular localization of isoforms. Hum. Mol. Genet. 12, 3181–3194 (2003).10.1093/hmg/ddg345 ↗
76. Elosegui-Artola, A. et al. Rigidity sensing and adaptation through regulation of integrin types. Nat. Mater. 13, 631–637 (2014).10.1038/nmat3960 ↗
77. Trepat, X. et al. Physical forces during collective cell migration. Nat. Phys. 5, 426–430 (2009).10.1038/nphys1269 ↗
78. Boudaoud, A. et al. FibrilTool, an ImageJ plug-in to quantify fibrillar structures in raw microscopy images. Nat. Protoc. 9, 457–463 (2014).10.1038/nprot.2014.024 ↗
79. Shenoy, V. B., Wang, H. & Wang, X. A chemo-mechanical free-energy-based approach to model durotaxis and extracellular stiffness-dependent contraction and polarization of cells. Interface Focus 6, 20150067 (2016).10.1098/rsfs.2015.0067 ↗
80. Alisafaei, F., Jokhun, D. S., Shivashankar, G. V. & Shenoy, V. B. Regulation of nuclear architecture, mechanics, and nucleocytoplasmic shuttling of epigenetic factors by cell geometric constraints. Proc. Natl Acad. Sci. USA 116, 13200–13209 (2019).10.1073/pnas.1902035116 ↗
81. Huber, F., Boire, A., López, M. P. & Koenderink, G. H. Cytoskeletal crosstalk: when three different personalities team up. Curr. Opin. Cell Biol. 32, 39–47 (2015).10.1016/j.ceb.2014.10.005 ↗
82. Brangwynne, C. P. et al. Microtubules can bear enhanced compressive loads in living cells because of lateral reinforcement. J. Cell Biol. 173, 733–741 (2006).10.1083/jcb.200601060 ↗
83. Schaedel, L., Lorenz, C., Schepers, A. V., Klumpp, S. & Köster, S. Vimentin intermediate filaments stabilize dynamic microtubules by direct interactions. Nat. Commun. 12, 3799 (2021).10.1038/s41467-021-23523-z ↗
84. Pogoda, K. et al. Depth-sensing analysis of cytoskeleton organization based on AFM data. Eur. Biophys. J. 41, 79–87 (2012).10.1007/s00249-011-0761-9 ↗
85. Tawada, K. & Sekimoto, K. Protein friction exerted by motor enzymes through a weak-binding interaction. J. Theor. Biol. 150, 193–200 (1991).10.1016/S0022-5193(05)80331-5 ↗
86. Sharma, V. vs-vivek/Nuclear_Mechano_Response: model for fibrillar adhesion dynamics govern the timescales of nuclear mechano-response via the vimentin cytoskeleton. Zenodo https://doi.org/10.5281/zenodo.19238182 (2026).10.5281/zenodo.19238182 ↗