How is the nucleus coupled to the cytoskeleton? 2018-02-05T15:48:42+00:00

How is the nucleus coupled to the cytoskeleton?

Cytoskeletal filaments bridge the nucleus to the plasma membrane, which in turn is anchored at sub-cellular sites to extracellular substrates via a plethora of proteins that form focal adhesions (FAs). FAs are points of cross-talk between transmembrane integrin receptors and the cytoplasmic filaments and thus are key sites for both biochemical and mechanotransduction pathways (reviewed in [1]). Linkage can be direct or via various adaptor proteins, providing structural support to both cellular and nuclear structures (reviewed in [2][3][4])

LINC-complexes-provide-structural-support

SUN and KASH domain proteins (mainly nesprins) provide the essential linkage between the three main cytoskeletal networks aend the nucleokeleton especially the nuclear lamina. Plectin acts as an intermediary linker connecting the intermediate filaments while a motor protein (e.g: kinesin) is generally involved in linking microtubules. INM- Inner nuclear membrane; ONM- Outer nuclear membrane; LBR- Lamin B receptor. Together these provide the outward pull that maintains the nucleus in a stretched state. Adapted from [21321324, 15688064, 21327104].

While actin filaments and microtubules constantly undergo remodeling by a contractile mechanism and dynamic instability respectively [5] domain proteins and the microtubule associated motor protein, dynein, thus providing structural integrity to the nucleus. From inside, the nuclear lamins and chromatin are anchored to the inner nuclear membrane through adaptor transmembrane SUN (Sad1p, UNC-84) proteins, which in turn are connected to KASH proteins [6]. Hence, though physically separated by the nuclear membrane (~50nm), the cytoplasm and nucleoplasm are linked by these evolutionarily conserved proteins, that mediate force transmission. Together these proteins are known as the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, [7][8]. The localization of KASH domain proteins like nesprin at outer nuclear envelope is affected by depletion of SUNs, which in turn depend on nuclear lamins [9][10][11]. These links are emerging to be pivotal in various physiological processes including cell migration and cytoskeletal integrity. Together, this network helps the cell cope with mechanical stress [12].

How does the cytoskeleton influence nuclear morphology and positioning?

Work by Mazumder et al. ascertained the active involvement of cytoskeletal forces in determining nuclear morphology. Change in nuclear size upon perturbation of actomyosin and microtubules affirmed their roles in exerting tensile and compressive forces respectively on the nucleus, correlating with their functions in the cellular context [13] [14], [15].

Furthermore, the ‘perinuclear cap’, which is composed of contractile actin bundles that bridge focal adhesions on either side of the nucleus, has been shown to tightly regulate the nuclear geometry [16]. These bundles pass apically to form a dome covering the top of the nucleus and are connected to the nucleus through the LINC complexes. They are completely absent in pluripotent cells whereas during differentiation, their formation accompanies expression and assembly of lamin A/C as well as the LINC complexes on the nuclear envelope [17]. As a result, the nuclear height and shape are under their control, suggesting a role in mediating mechanosensitive processes such as motility and polarization [18].

Besides nuclear morphology, cytoplasmic forces also govern nuclear positioning in the cell by regulating the translational and rotational dynamics [19]
[20]. Positioning is accomplished by the physical connection by nuclear envelope proteins SUN-KASH-lma1 between centromeric heterochromatin regions and the microtubule network [21]. With the centromere providing tensional force on the microtubules that undergo dynamic instability, dynein motors mediate the rotation [22][23]. Actin links via SUN-nesprin are implicated in force transduction for nuclear movement during cell migration [24]. Regulation of nuclear position and orientation is critical in many cellular processes such as migration, cell division, polarization, fertilization and differentiation [20][22].

View All

Latest Findings

Protein Info

References

  1. Geiger B, Spatz JP, and Bershadsky AD. Environmental sensing through focal adhesions. Nat. Rev. Mol. Cell Biol. 2009; 10(1):21-33. [PMID: 19197329]
  2. Wang N, Tytell JD, and Ingber DE. Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nat. Rev. Mol. Cell Biol. 2009; 10(1):75-82. [PMID: 19197334]
  3. Geiger B, Bershadsky A, Pankov R, and Yamada KM. Transmembrane crosstalk between the extracellular matrix--cytoskeleton crosstalk. Nat. Rev. Mol. Cell Biol. 2001; 2(11):793-805. [PMID: 11715046]
  4. Boban M, Braun J, and Foisner R. Lamins: 'structure goes cycling'. Biochem. Soc. Trans. 2010; 38(Pt 1):301-6. [PMID: 20074079]
  5. Tang CW, Maya-Mendoza A, Martin C, Zeng K, Chen S, Feret D, Wilson SA, and Jackson DA. The integrity of a lamin-B1-dependent nucleoskeleton is a fundamental determinant of RNA synthesis in human cells. J. Cell. Sci. 2008; 121(Pt 7):1014-24. [PMID: 18334554]
  6. Furukawa K, Ishida K, Tsunoyama T, Toda S, Osoda S, Horigome T, Fisher PA, and Sugiyama S. A-type and B-type lamins initiate layer assembly at distinct areas of the nuclear envelope in living cells. Exp. Cell Res. 2009; 315(7):1181-9. [PMID: 19210986]
  7. Coffinier C, Chang SY, Nobumori C, Tu Y, Farber EA, Toth JI, Fong LG, and Young SG. Abnormal development of the cerebral cortex and cerebellum in the setting of lamin B2 deficiency. Proc. Natl. Acad. Sci. U.S.A. 2010; 107(11):5076-81. [PMID: 20145110]
  8. Schirmer EC, and Foisner R. Proteins that associate with lamins: many faces, many functions. Exp. Cell Res. 2007; 313(10):2167-79. [PMID: 17451680]
  9. Wagner N, and Krohne G. LEM-Domain proteins: new insights into lamin-interacting proteins. Int. Rev. Cytol. 2007; 261:1-46. [PMID: 17560279]
  10. Wilson KL, and Berk JM. The nuclear envelope at a glance. J. Cell. Sci. 2010; 123(Pt 12):1973-8. [PMID: 20519579]
  11. Dahl KN, Kahn SM, Wilson KL, and Discher DE. The nuclear envelope lamina network has elasticity and a compressibility limit suggestive of a molecular shock absorber. J. Cell. Sci. 2004; 117(Pt 20):4779-86. [PMID: 15331638]
  12. Ahmed S, and Brickner JH. Regulation and epigenetic control of transcription at the nuclear periphery. Trends Genet. 2007; 23(8):396-402. [PMID: 17566592]
  13. Towbin BD, Meister P, and Gasser SM. The nuclear envelope--a scaffold for silencing? Curr. Opin. Genet. Dev. 2009; 19(2):180-6. [PMID: 19303765]
  14. Ingber DE. Tensegrity-based mechanosensing from macro to micro. Prog. Biophys. Mol. Biol. 2008; 97(2-3):163-79. [PMID: 18406455]
  15. Mazumder A, and Shivashankar GV. Emergence of a prestressed eukaryotic nucleus during cellular differentiation and development. J R Soc Interface 2010; 7 Suppl 3:S321-30. [PMID: 20356876]
  16. Zastrow MS, Flaherty DB, Benian GM, and Wilson KL. Nuclear titin interacts with A- and B-type lamins in vitro and in vivo. J. Cell. Sci. 2006; 119(Pt 2):239-49. [PMID: 16410549]
  17. Zhong Z, Wilson KL, and Dahl KN. Beyond lamins other structural components of the nucleoskeleton. Methods Cell Biol. 2010; 98:97-119. [PMID: 20816232]
  18. Young KG, and Kothary R. Spectrin repeat proteins in the nucleus. Bioessays 2005; 27(2):144-52. [PMID: 15666356]
  19. Holaska JM, Kowalski AK, and Wilson KL. Emerin caps the pointed end of actin filaments: evidence for an actin cortical network at the nuclear inner membrane. PLoS Biol. 2004; 2(9):E231. [PMID: 15328537]
  20. Pederson T, and Aebi U. Actin in the nucleus: what form and what for? J. Struct. Biol. 140(1-3):3-9. [PMID: 12490148]
  21. Morton NE. Parameters of the human genome. Proc. Natl. Acad. Sci. U.S.A. 1991; 88(17):7474-6. [PMID: 1881886]
  22. Bustamante C, Bryant Z, and Smith SB. Ten years of tension: single-molecule DNA mechanics. Nature 2003; 421(6921):423-7. [PMID: 12540915]
  23. Luger K, and Hansen JC. Nucleosome and chromatin fiber dynamics. Curr. Opin. Struct. Biol. 2005; 15(2):188-96. [PMID: 15837178]
  24. Marenduzzo D, Micheletti C, and Cook PR. Entropy-driven genome organization. Biophys. J. 2006; 90(10):3712-21. [PMID: 16500976]