Editors' ChoiceCell Biology

Nuclei Sense the Force

Sci. Signal.  15 Apr 2014:
Vol. 7, Issue 321, pp. ec100
DOI: 10.1126/scisignal.2005366

Mechanical forces—such as compression, shearing, or cell-cell contact—induce intracellular changes that affect motility, polarity, and survival. Cell surface tension signals are transduced to the nucleus through the cytoskeleton and the LINC complex, a nuclear transmembrane protein network that anchors the nuclear envelope and the nuclear lamina to the actin cytoskeleton. The RhoA pathway mediates cytoskeletal actin remodeling in response to mechanical force sensed by integrins at the cell surface, and RhoA can localize to the nucleus to regulate nuclear actin. Guilluy et al. found that the nucleus itself stiffens in response to mechanical stress. The authors used magnetic tweezers to apply a force to isolated nuclei (from HeLa cells, human umbilical vein endothelial cells, or MRC5 fibroblast cells) bound to magnetic beads coated in an antibody against nesprin-1, a component of the LINC complex. Application of successive magnetic pulses progressively decreased displacement of the beads from the nuclei, which suggested that the nuclei were stiffer, whereas no changes in displacement were observed when beads were coated in poly–lysine or antibody against a nuclear pore protein. Additionally, the nuclei subjected to the magnetic pulses exhibited activated RhoA and the tyrosine kinase Src and had phosphorylated emerin, an inner nuclear membrane protein. However, the addition of agents that inhibit RhoA, the Rho-associated kinase (ROCK), or the formation of actin filaments to isolated nuclei did not prevent nuclear stiffening, whereas depletion of emerin in cells before isolating the nuclei did. Isolation of nuclei from cells in which various tyrosine kinases were pharmacologically inhibited or cells expressing phosphorylation-resistant tyrosine-to-phenylalanine emerin mutants indicated that exposure of these nuclei to force and the induction of nuclear stiffening required Src-dependent phosphorylation of emerin at Tyr74 and Tyr95. Expression of phosphorylation-resistant emerin decreased the induction of mechanosensitive gene expression, the formation of cytosolic stress fibers, and the aspect ratio (the cells were rounder, which indicates a change in cell polarity) of MRC5 fibroblasts and impaired migration in HeLa cells. These findings identify a mechanism of mechanotransduction in the nucleus and suggest that this nuclear response is crucial for the cellular response to mechanical force.

C. Guilluy, L. D. Osborne, L. Van Landeghem, L. Sharek, R. Superfine, R. Garcia-Mata, K. Burridge, Isolated nuclei adapt to force and reveal a mechanotransduction pathway in the nucleus. Nat. Cell Biol. 16, 376-381 (2014). [PubMed]