Differential basal-to-apical accessibility of lamin A/C epitopes in the nuclear lamina regulated by changes in cytoskeletal tension

Abstract

Nuclear lamins play central roles at the intersection between cytoplasmic signalling and nuclear events. Here, we show that at least two N- and C-terminal lamin epitopes are not accessible at the basal side of the nuclear envelope under environmental conditions known to upregulate cell contractility. The conformational epitope on the Ig-domain of A-type lamins is more buried in the basal than apical nuclear envelope of human mesenchymal stem cells undergoing osteogenesis (but not adipogenesis), and in fibroblasts adhering to rigid (but not soft) polyacrylamide hydrogels. This structural polarization of the lamina is promoted by compressive forces, emerges during cell spreading, and requires lamin A/C multimerization, intact nucleoskeleton-cytoskeleton linkages (LINC), and apical-actin stress-fibre assembly. Notably, the identified Igepitope overlaps with emerin, DNA and histone binding sites, and comprises various laminopathy mutation sites. Our findings should help deciphering how the physical properties of cellular microenvironments regulate nuclear events.

Squish and squeeze — the nucleus as a physical barrier during migration in confined environments

“…Loss of B-type lamins impairs migration of neurons, which lack A-type lamins, in the developing brain, and this effect is thought to be caused by defects connecting the nuclear interior and cytoplasm [48,49]. Given recent reports that lamin A/C levels and organization can vary in response to substrate stiffness and cytoskeletal tension [41,50,51], it is intriguing to speculate that cells could also dynamically adjust their nuclear stiffness during migration.…”

Causes and consequences of nuclear envelope alterations in tumour progression

“…In addition to modulating total levels of lamin A/C, the physical properties of the microenvironment can also affect intranuclear lamina organization. For example, with increased substrate stiffness and cell spreading, a lamin A/C conformational epitope in the Ig-domain becomes masked in the basal portion of the NE (Ihalainen et al, 2015), suggesting structural rearrangements within the lamina that could further impact interactions of lamins with chromatin and other binding partners. These studies demonstrate that organization and levels of lamin A/C are both dynamically regulated in response to the physical microenvironment and can modulate cellular mechanotransduction signalling.…”

Cell Mechanosensitivity Is Enabled by the LINC Nuclear Complex

“…Maintenance of nuclear shape and lamin A/C polarization by the compressive forces generated by the perinuclear actin cytoskeleton [66, 67] suggests another level of cytomechanical control on heterochromatin: specifically, physical changes in the nucleoskeleton may alter the nonrandom organization of chromosomes [68]. The nucleoskeleton can adapt to mechanical qualities of the surrounding matrix as well as dynamic forces.…”