Nuclear mechanosensing

Abstract

Structural links from the nucleus to the cytoskeleton and to the extracellular environment play a role in direct mechanosensing by nuclear factors. Here, we highlight recent studies that illustrate nuclear mechanosensation processes ranging from DNA repair and nuclear protein phospho-modulation to chromatin reorganization, lipase activation by dilation, and reversible rupture with the release of nuclear factors. Recent progresses demonstrate that these mechanosensing processes lead to modulation of gene expression such as those involved in the regulation of cytoskeletal programs and introduce copy number variations. The nuclear lamina protein lamin A has a recurring role, and various biophysical analyses prove helpful in clarifying mechanisms. The various recent observations provide further motivation to understand the regulation of nuclear mechanosensing pathways in both physiological and pathological contexts.

Figure 1.. Nucleus mechanosensing.

Schematic showing recent evidence of nucleus mechanosensing in factors and processes that range from DNA repair and nuclear protein phosphorylation to chromatin reorganization, nuclear membrane dilation-activated proteins, and reversible rupture with the release of various nuclear factors. Mechanical perturbations and hyperosmotic challenge lead to chromatin condensation, followed by translocation and activation of ATR to the nuclear peripheral region. Tension and compression applied to the nucleus during cell spreading induces intermingling of chromosome territories, which might pack differently in different nuclear shapes. Nuclear membrane stretching upon hypo-osmotic swelling and compression causes cPLA2 to localize to the nuclear membrane, where it activates. Pulling forces on nesprin-1 lead to phosphorylation of emerin, which is essential to the nucleus mechanoresponse and other downstream mechanotransdruction pathways, including transcription co-activator YAP1 localization. Similar to collagen-1 [47], high nuclear tension on the lamin A inhibits the access of kinases, preventing phosphorylation of the lamins, which, in turn, suppress lamin A disassembly and digestion. Migration through constrained spaces and lamin A deficiency cause transient nuclear rupture, which compromises nuclear/cytoplasmic compartmentalization and may thereby inhibit many nuclear processes, including DNA repair.

Figure 2.. Nuclear volume modulation with osmotic challenge and relocalization of mobile nuclear factors.

(A) Osmotically induced cell and nuclear changes can be predicted by a standard van der Waals equation that lacks the attraction term [24], where ΔV is the change in cell or nuclear volume and Δπ is the change in osmotic pressure. (B) Resembling previous findings in ATR [23], other nuclear mobile proteins may also translocate after hyperosmotic challenge.

Figure 3.. Nuclear tension dictates lamin A turnover.

(A) Tension exerted by the stress fibers flattens and smooths the nucleus of cells cultured on stiff substrate. (B) High tension on the lamina inhibits the access of kinases to lamin A, preventing phosphorylation of the lamins, which is essential for lamin A disassembly and turnover. (C) High tension-induced lamin A integrity helps retain SUN2 at the nuclear envelope; this shift of SUN2 from the endoplasmic reticulum into the nucleus also facilitates RARG entry and retention.

Figure 4.. Gene circuit of tension-regulated lamin A expression.

(A) Tension-dependent phosphorylation and turnover feeds into transcriptional regulation. Lamin A,C protein transcriptionally regulates LMNA via the retinoic acid pathway (through SUN2 as a mediator, α) and also MYH9 via the SRF pathway (through nuclear actin). On stiff matrix, non-phosphorylated, contraction-competent myosins positively regulate lamin A,C, favoring assembly and opposing degradation that occurs on soft matrices. (B) A simple model was generated based on the gene circuit: time evolution of LMNA mRNA (M) level is dependent on the LMNA protein level (P), whereas the protein level itself is regulated by a tension-dependent degradation term, h. The model shows that tension-regulated protein turnover can produce steady-state protein levels that scale with cell tension. Trajectories of lamin A message and protein as the model converge from a range of initial conditions to a single steady-state solution appropriate to the tension.