Scientists have learned that besides building a cell's protein factories, nuclolus serves more broadly as a control center for cellular growth and health.
In the last several years amidst a flurry of research, researchers discovered that the nucleolus behaves like a liquid with the consistency of honey. Yet somehow, this biological droplet maintains a complex, compartmentalized internal structure.
A new study presents a solution to the paradox of nucleolar assembly and internal organization. Their paper published in Cell, shows that the constituent proteins and RNA of nucleoli spontaneously assemble themselves into three distinct, liquid layers, thanks to their differing properties such as surface tension and viscosity. Rather like how oil and water can coexist yet remain separate, the nucleolus develops liquid subcompartments, which enable its critical functions.
The researchers investigated nucleoli by conducting experiments with purified nucleolar proteins as well as living frog egg cells, roundworms and cultured cells, plus some computer modeling.
The work on the frog eggs took advantage of the fact that the eggs possess multiple, large nucleoli, easing the organelle's observation and manipulation. In these eggs, the nucleoli normally do not come into contact because of an elastic actin network. Scientists incubated them in a pharmacological drug to break down the actin, allowing nucleoli to contact one another, and observed their contents fuse, much like how two droplets of water coalesce into a larger drop. By analyzing these fusion events, the researchers teased out the differing biophysical properties for the respective nucleolar layers.
Meanwhile, collaborators lab found that droplets of the two main nucleolar proteins, dubbed FIB1 and NPM1, would not blend into each other as a homogenous fluid. Instead, because FIB1's surface tension was higher than NPM1, the former became engulfed by the latter, precisely mimicking the nucleolar structure seen in living cells. As a demonstration of this phenomenon, the researchers also created similar multi-phase drops --liquids embedded within other liquids -- using vegetable oil and silicone oil in water.
Altogether, the data handily explain how the individual subcompartments of the nucleolus nestle inside of each other, somewhat like a Russian matryoshka or "nesting" doll.
For the nucleolus, this layered form follows function. Newly made RNA molecules proceed from the organelle's core into the middle, then outer components, receiving modifications as they do so, as if on an assembly line. Like a factory, nucleoli churn out these RNA bits, which after leaving the nucleolus ultimately enter into the cell's cytoplasm and link up to form structures called ribosomes. Factories in their own right, these ribosomes manufacture a cell's many thousands of proteins.
Beyond making ribosomes, the nucleolus has lately emerged as a hub for coordinating cellular growth, helping to regulate cell division and even setting the timing of a cell's self-destruction in reaction to stress or damage. Given this centrality, the nucleolus is also increasingly being recognized for roles in disease. For instance, during certain illnesses, nucleoli may lose some of their normal liquidness. If the faulty nucleoli become more fibrous, throwing off kilter the smooth flow of RNA through their chambers, this could contribute to heart and neurological diseases.
Another major disease nucleoli figure prominently in is cancer. In malignant cells, hijacked nucleoli overproduce proteins to fuel out-of-control, rapid divisions. Oncologists routinely grade cancer cells' aggressiveness in part on the degree of their misshapen and bloated nucleoli.
Assembly of nucleolus unraveled!
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