Mechanotransduction and nuclear function

Abstract

Many signaling pathways converge on the nucleus to regulate crucial nuclear events such as transcription, DNA replication and cell cycle progression. Although the vast majority of research in this area has focused on signals generated in response to hormones or other soluble factors, the nucleus also responds to mechanical forces. During the past decade or so, much has been learned about how mechanical force can affect transcription, as well as the growth and differentiation of cells. Much has also been learned about how force is transmitted via the cytoskeleton to the nucleus and then across the nuclear envelope to the nuclear lamina and chromatin. In this brief review, we focus on some of the key proteins that transmit mechanical signals across the nuclear envelope.

Figure 1. The nuclear lamina and cytoskeleton are highly interconnected

Transmission electron micrograph of a HeLa cell, after removal of membranes and nucleic acids, showing nuclear filaments interconnecting with the cytoskeleton. Reprinted from Cell, vol. 29, Capco DG, Wan KM, Penman S, “The nuclear matrix: three-dimensional architecture and protein composition”, 847-858, 1982, with permission from Elsevier (license#: 3727211229007)

Figure 2. LINC complexes tether the nucleus

The nuclear envelope is cutaway to expose the nuclear lamina and underlying chromatin. Inner nuclear envelope proteins emerin, SUN1/2, and Samp1 regulate interactions with KASH domain-containing Nesprin family members, 1-4. Nesprins associate with the cytoskeleton directly and indirectly via adaptor proteins and molecular motors.

Figure 3. Force transduction to the nucleus and back

Schematic demonstrating the flow of cellular force from the plasma membrane to the nucleus. Force is manifested as distortion of the plasma membrane or proteins within it. Tension is transmitted to the different systems of the cytoskeleton and transmitted to the nucleus via the LINC complex. In turn, the LINC complex transmits force across the nuclear membrane to the nuclear lamina and to chromatin. The nucleus rapidly responds to force application at the nuclear lamina and this response is conveyed back through these same elements.