The nuclear envelope is essential to protect the genome and to regulate traffic in and out of the nucleus. Romanauska and Köhler initially asked a simple, yet fundamental question: what makes the cell nucleus round? Despite variations in nuclear shape in different cell types, from spherical to ovoid and sometimes multilobed, cell nuclei are typically devoid of edges.
The two scientists suspected that the nature of lipids, more specifically their saturation state, may play a role in keeping nuclei round. Lipid saturation describes whether the lipid's acyl chains are linear or kinked. When acyl chains are unsaturated and kinked, they confer membrane elasticity and fluidity. Conversely, saturated lipids, which are straight and can pack tightly against each other, make membranes rigid and viscous. At least this was the assumption based on in vitro experiments with synthetic membranes. Whether these assumptions would hold in cells had not been tested, because altering lipid saturation in a controlled manner within cells is challenging.
Romanauska and Köhler succeeded in engineering a circuit of enzymes that increased the lipid saturation level in cells and then used advanced multimodal imaging to observe the outcomes. The consequences were stunning: cell nuclei that were previously spherical, now became angular, approximating the shape of a polyhedron. Nuclear membranes had become rigid and planar, and they exhibited a unique lipid segregation pattern into ordered and disordered phases.
Notably, nuclear pore complexes, huge channels embedded into the nuclear envelope, were excluded from the ordered phase and occupied the disordered phase, which is enriched in the remaining, unsaturated (kinked) lipids. Moreover, when the balance between saturated and unsaturated lipids was tilted towards saturation, nuclear pore complexes became defective, and transport between the nucleus and cytoplasm was impaired. This showed that nuclear pore complexes have specific lipid requirements to function. Intriguingly, lipid droplets, which are ubiquitous fat-storing organelles, were identified as key players in sequestering and buffering the effects of saturated lipids.
As Anete Romanauska puts it: "Our research uncovers a fundamental connection between a very subtle change in lipid chemistry and the integrity of the entire cell nucleus. This has broad implications for understanding how nuclear envelope function can become endangered by the wrong type of lipids.”
One of the key findings of the study is that oxygen deprivation perturbs the balance of saturated and unsaturated lipids, resulting in a similar lipidomic fingerprint and nuclear phenotype as that seen in the genetically engineered cells. Unexpectedly, the angular nuclei in both these situations become brittle and frequently rupture, a catastrophic event where cytoplasmic material leaks into the nucleus. This finding may be relevant for cancer biology, because tumor cells often become deprived of oxygen.
The new study uncovers essential, lipid-centric mechanisms that govern nuclear envelope architecture and function. It also shows a way towards therapeutic interventions that could specifically damage cancer cells. What Romanauska and Köhler show is that the formation of a rounded and elastic nuclear envelope emerges as the outcome of a precise choreography, where the molecular dance of saturated and unsaturated lipids in a membrane confers both elasticity and robustness to the cell nucleus.
Anete Romanauska & Alwin Köhler: Lipid saturation controls nuclear envelope function. Nature Cell Biology (2023)