Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Protein droplets keep neurons at the ready and immune system in balance

16.08.2018

Inside cells, where DNA is packed tightly in the nucleus and rigid proteins keep intricate transport systems on track, some molecules have a simpler way of establishing order. They can self-organize, find one another in crowded spaces, and quickly coalesce into droplets­­ - like oil in water.

Now, new discoveries from Howard Hughes Medical Institute (HHMI) scientists reported July 5, 2018, in the journal Science demonstrate that these droplets do more than keep cells' interiors tidy.


In this 3-D reconstruction, synaptic vesicles (blue spheres) cluster together in a nerve terminal near the synaptic junction (red). Scale bar equals 0.4 micrometers.

Credit: Pietro De Camilli Lab

In one study, HHMI Investigator Pietro De Camilli and colleagues have shown how liquid droplets inside neurons keep signals racing through the brain. In the other, a team led by HHMI Investigator Zhijian "James" Chen has discovered that droplets of a danger-sensing enzyme generate signals that launch an immune response.

The formation of these droplets is a phenomenon known as phase separation. In the last decade, biologists have watched proteins and RNA molecules rapidly organize themselves into droplets inside test tubes and spotted liquid-like droplets inside cells.

But it hasn't always been clear what, if any, advantages these droplets provide. The new discoveries from De Camilli and Chen offer an answer - a clear link between phase separation and biological function.

Neural droplets

In his lab at the Yale School of Medicine, De Camilli studies how neurons manage the neurotransmitters that relay signals between neighboring cells. Inside cells, these signaling molecules reside in tiny membrane-bound spheres called synaptic vesicles. When an incoming message arrives, vesicles release their contents into the synapse, the space across which a cell communicates with its neighbor.

Each cell can store thousands of vesicles in structures called nerve terminals. At times, a single terminal may need to release more than 100 synaptic vesicles in a second. So it's crucial that the reserves are readily accessible, De Camilli says.

Using an electron microscope, scientists have seen that synaptic vesicles cluster together in compact structures. In the 1980s, as a postdoctoral researcher in the laboratory of Paul Greengard, De Camilli found that these clusters are highly enriched in a protein associated with the vesicle surface. The researchers called the protein synapsin. "We hypothesized that synapsin may help keep vesicles together, but we never really understood how it worked," De Camilli says.

No membrane or structure encases the clusters, and De Camilli says he wondered for decades what held them together. When he heard about other biologists' phase separation discoveries, he suspected the phenomenon might also apply to synapsin.

Postdoctoral researcher Dragomir Milovanovic was struck by some features of synapsin that resemble those of other proteins that can phase separate. He dropped a solution of fluorescent synapsin molecules onto a cover slip and watched them quickly coalesce into droplets. Occasionally, two droplets merged into one, just like oil droplets finding one another in water. In other experiments, Milovanovic observed individual synapsin molecules moving freely between droplets. Just as the scientists had guessed, synapsin was behaving like a fluid.

Milovanovic went on to show that synapsin can even organize vesicle-like structures - like those inside nerve cells - into droplets. What's more, the droplets rapidly break up when exposed to a signal that triggers neurotransmitter release. "You go from beautiful droplets to the complete disassembly of droplets," De Camilli says, explaining that this mimics the natural dispersion of synaptic vesicles that occurs when nerve cells communicate.

In nerve cells, droplets of synaptic vesicles offer a clear advantage, he says: a ready supply of neurotransmitter messengers. The finding explains how neurons can keep up when the demand for neurotransmitter release is high.

An immune alert

At the University of Texas Southwestern Medical Center, Chen's work with liquid droplets helped explain a different puzzle: how a DNA-sensing enzyme alerts the immune system to infection. That enzyme is cyclic GMP-AMP synthase, or cGAS, which Chen's lab discovered in 2012.

The enzyme floats in the cytoplasm of cells and switches on when it encounters DNA. Since a cell's own genes are contained in its nucleus and mitochondria, DNA in the cytoplasm is a signal that something is amiss ­- usually, that a pathogen is present. cGAS responds by generating cGAMP, a messenger molecule that calls on the body's first line of defense - the innate immune system - to counter the suspected threat.

A few oddities about the enzyme's behavior were, at first, difficult to explain. Why, for example, did long DNA molecules activate it more efficiently than short ones? A clue came from the concentrated speckles that Chen and his colleagues had seen the enzyme form inside cells when bound to DNA. Perhaps the enzyme was undergoing phase separation, they thought.

Sure enough, when graduate student Mingjian Du mixed cGAS and DNA in a test tube, he saw characteristically liquid behavior. The DNA-bound enzyme formed compact droplets, molecules diffused from one droplet to the next, and occasionally two droplets merged into one. "We suspected this might happen, but it's quite striking when you see that it happens in such an efficient manner," Chen says.

Du's experiments established that the enzyme forms droplets only in the presence of DNA. These droplets are critical for pathogen sensing - they appear to act as microreactors, bringing the enzyme together with everything it needs to generate the immune-activating messenger molecule, Chen says. Longer pieces of DNA are better at promoting droplet formation than short ones.

And because DNA must be present above a threshold level before these droplets form, cGAS rarely calls the innate immune system to action unnecessarily. Waiting until enough DNA is present to trigger phase separation effectively lets the enzyme distinguish friends from foe, Chen says.

Sometimes, he notes, cells fail to achieve that fine balance. Then, cGAS, and consequently the immune system, overreact to a cell's own DNA, resulting in autoimmune diseases such as lupus or arthritis. Understanding how phase separation regulates this enzyme may help scientists devise ways to correct such problems.

###

Dragomir Milovanovic, Yumei Wu, Xin Bian, and Pietro De Camilli, "A liquid phase of synapsin and lipid vesicles." Science 361, no. 6402 (August 2018): 604, doi: 10.1126/science.aat5671

Mingjian Du and Zhijian Chen, "DNA-induced liquid phase condensation of cGAS activates innate immune signaling." Science. July 5, 2018. doi: 10.1126/science.aat1022

Media Contact

Meghan Rosen
rosenm2@hhmi.org
301-215-8859

 @HHMINEWS

http://www.hhmi.org 

Meghan Rosen | EurekAlert!
Further information:
https://www.hhmi.org/news/protein-droplets-keep-neurons-at-the-ready-and-immune-system-in-balance
http://dx.doi.org/10.1126/science.aat5671

Further reports about: DNA HHMI Protein droplets enzyme immune immune system nerve cells synaptic vesicles vesicles

More articles from Life Sciences:

nachricht Chip-based optical sensor detects cancer biomarker in urine
06.12.2019 | The Optical Society

nachricht Scientist identify new marker for insecticide resistance in malaria mosquitoes
06.12.2019 | Liverpool School of Tropical Medicine

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Developing a digital twin

University of Texas and MIT researchers create virtual UAVs that can predict vehicle health, enable autonomous decision-making

In the not too distant future, we can expect to see our skies filled with unmanned aerial vehicles (UAVs) delivering packages, maybe even people, from location...

Im Focus: The coldest reaction

With ultracold chemistry, researchers get a first look at exactly what happens during a chemical reaction

The coldest chemical reaction in the known universe took place in what appears to be a chaotic mess of lasers. The appearance deceives: Deep within that...

Im Focus: How do scars form? Fascia function as a repository of mobile scar tissue

Abnormal scarring is a serious threat resulting in non-healing chronic wounds or fibrosis. Scars form when fibroblasts, a type of cell of connective tissue, reach wounded skin and deposit plugs of extracellular matrix. Until today, the question about the exact anatomical origin of these fibroblasts has not been answered. In order to find potential ways of influencing the scarring process, the team of Dr. Yuval Rinkevich, Group Leader for Regenerative Biology at the Institute of Lung Biology and Disease at Helmholtz Zentrum München, aimed to finally find an answer. As it was already known that all scars derive from a fibroblast lineage expressing the Engrailed-1 gene - a lineage not only present in skin, but also in fascia - the researchers intentionally tried to understand whether or not fascia might be the origin of fibroblasts.

Fibroblasts kit - ready to heal wounds

Im Focus: McMaster researcher warns plastic pollution in Great Lakes growing concern to ecosystem

Research from a leading international expert on the health of the Great Lakes suggests that the growing intensity and scale of pollution from plastics poses serious risks to human health and will continue to have profound consequences on the ecosystem.

In an article published this month in the Journal of Waste Resources and Recycling, Gail Krantzberg, a professor in the Booth School of Engineering Practice...

Im Focus: Machine learning microscope adapts lighting to improve diagnosis

Prototype microscope teaches itself the best illumination settings for diagnosing malaria

Engineers at Duke University have developed a microscope that adapts its lighting angles, colors and patterns while teaching itself the optimal...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

The Future of Work

03.12.2019 | Event News

First International Conference on Agrophotovoltaics in August 2020

15.11.2019 | Event News

Laser Symposium on Electromobility in Aachen: trends for the mobility revolution

15.11.2019 | Event News

 
Latest News

Solving the mystery of carbon on ocean floor

06.12.2019 | Earth Sciences

Chip-based optical sensor detects cancer biomarker in urine

06.12.2019 | Life Sciences

A platform for stable quantum computing, a playground for exotic physics

06.12.2019 | Information Technology

VideoLinks
Science & Research
Overview of more VideoLinks >>>