- Press Release Distribution

Switching off the cytokine storm

EMBL Grenoble and University of Geneva researchers shed light on the molecular activation of the MAP kinase p38α, the final ‘switch’ triggering the inflammatory response

Switching off the cytokine storm
( Constant exposure of cells to stressing agents, such as pathogens, may disturb an organism’s normal functioning. To fight stress, cells have developed several coping mechanisms, including the inflammatory response. 

While inflammation is necessary, too much of it can impair cell and organ function. This is the case with cytokine storms – inflammatory cascades during an infection that can spiral out of control and lead to severe disease and even death, as recently highlighted during the COVID-19 pandemic.

In a new paper published in Science, EMBL Grenoble and University of Geneva researchers provide essential insights on a protein called p38α, belonging to the Mitogen Activated Protein Kinase (MAPK) family, which is an important cellular ‘switch’ triggering the inflammatory response. They have obtained the first structure of p38α being activated by another regulatory protein kinase – MKK6 – opening up new directions to develop drugs to stop cytokine storms.

The final switch: a drug target

Matthew Bowler, a researcher at EMBL Grenoble, has been studying kinases for more than a decade. This group of enzymes plays an important role in regulating complex processes in the cell by acting as a ‘switch’ to transmit signals and activate gene expression. They do so by phosphorylation – adding a chemical group, phosphate, to other molecules to modulate their function.

Bowler’s work particularly focuses on MAP kinases, key players involved in the inflammatory response. Inflammation is switched on via a series of kinases, which activate each other in a cascade of reactions, the final kinase in the series being responsible for activating gene transcription required for inflammation. This process releases cytokines, pro-inflammatory signalling molecules, which, in case of overactivation, can lead to cytokine storms.

This kinase chain reaction is well regulated and is similar to a logic circuit: the inflammation response requires specific buttons to be switched on, ultimately activating p38α – the meeting point where all the signals converge and the last switch of the inflammatory process.

Because the kinase chain reaction can come from different ‘branches’ of the logic circuit, this last switch is a particularly relevant drug target. The inflammatory response is regulated by p38α and is highly activated during a cytokine storm. Inactivating it could prevent inflammation from occurring, instead of trying to treat it while it is already underway.

Protein kinases, including p38α, have therefore been heavily studied. The first protein kinase structure was solved 30 years ago – a landmark in the field – and many more structures have followed, with over 7,000 structures now available in the Protein Data Bank.

However, important parts of the puzzles are still missing. “Structural biologists have obtained detailed information on the structure and functions of protein kinases, but mostly in isolation. So we don’t really know how these enzymes are activated along the chain reaction,” explained Bowler.

Without this essential information about how the activation is triggered, drugs have mostly targeted the kinases’ nucleotide-binding site – a common and well-known pocket present in all kinases, where the phosphate transfer occurs. The lack of drug specificity due to a common binding site across kinases means that a drug designed to stop one kinase from signalling could also stop others. This presents a problematic side effect, considering the essential role of kinases as key regulators in cellular processes.

“There are many molecules that have been designed to target p38α, especially its nucleotide-binding site, but none have yet made it past clinical trials due to this lack of specificity,” added Bowler. 

Cracking the activation mechanism

Bowler and a former PhD student in his lab, Erika Pellegrini, have therefore been investigating the interactions between p38α and MKK6 - the kinase which activates it - since 2009.  But studying the interaction between kinases proves to be extremely complex. “These enzymes are very dynamic molecules; they transmit important signals and need to act quickly. In the case of p38α, it has to go into the nucleus and activate lots of other different proteins,” said Bowler.

They were hampered by the fact that the interactions of the MKK6-p38α complex cannot be determined by macromolecular crystallography, a structural biology technique often employed to investigate proteins but that is particularly challenging to apply in the case of such dynamic proteins.

Recent developments in cryo-electron microscopy (cryo-EM), particularly during the last decade, raised new hopes. In 2016, Bowler and new PhD student and first author of the paper, Pauline Juyoux, decided to switch to this technique – even though the protein complex was at the time considered too small for cryo-EM analysis. They were supported by Pellegrini, who had acquired expertise in this technique.

Tenacity and collaboration were key contributors to project success. "There were a lot of ups and downs, but there were always inspiring people or moments – one of these being particularly memorable,” remembered Juyoux. “We obtained the first low-resolution 3D negative stain model on the exact same day that the Nobel Prize was announced for cryo-EM in 2017. It gave us a boost of motivation!”

Using cryo-EM and complementary techniques, such as X-ray crystallography and small-angle X-ray scattering (SAXS) at the European Synchrotron Radiation Facility and Diamond Light Source, the team managed to obtain the 3D structure of the complex and identify a previously unknown docking site where the two enzymes interact – crucial information for understanding how p38α is activated. “This could be an interesting target for inhibitors that block this specific interaction, and consequently the signal triggering the inflammatory response,” explained Juyoux.

A collaboration with the Gervasio Lab from the University of Geneva, which uses molecular dynamics simulations, supported Bowler, Pellegrini, and Juyoux in giving further insight into how the two kinases interact. “They showed that the model we had generated was compatible with the enzymatic activity and that the phosphorylation site was at the right distance from the active site,” explained Juyoux. “They also classified the different types of conformations of the complex to show how they assemble.” 

Crucially, by comparing these simulations with the SAXS data they were able to model how the two proteins interact prior to catalysis. “The beauty of combining the state-of-the-art simulations with SAXS and cryo-EM data through advanced statistical approaches is that we can ‘see’ the dance of the two kinases approaching one another, while knowing that what we see in the computer is fully supported by all the experimental data available,” explained Francesco Gervasio. “The simulations required several months of supercomputing time generously allocated by the Swiss National Supercomputing Centre,” he continued, “But it was well worth it, given the relevance of the final results.”   

These results provide an alternative drug target site to explore and also open the door to studying similar processes in two other families of MAP kinases: ERK kinases – which are involved in cancer – and JNK kinases – also involved in inflammation, especially in Alzheimer’s disease.

“Kinases are very similar to one another in terms of sequence and structure, but we don't know how and why they respond or send a specific signal,” said Juyoux, whose current research project as a postdoctoral fellow at Institut de Biologie Structurale in Grenoble focuses on JNK kinases. “Comparing these different families of kinases could help explain the specificity of interactions and lead the way to new therapeutic approaches.”



[Attachments] See images for this press release:
Switching off the cytokine storm Switching off the cytokine storm 2 Switching off the cytokine storm 3


Specialised gut immune cells pinpointed that can limit progression of inflammatory bowel disease

Researchers at the Francis Crick Institute, King’s College London and Guy’s and St Thomas’ NHS Foundation Trust have characterised a specialised type of immune cell, which plays a key role in protecting and repairing the cells in the healthy human gut. These protective immune cells are depleted in inflammatory bowel disease (IBD), leaving patients vulnerable to disease progression and severe complications. The findings could lead to better clinical management and treatment options for people living ...

Researchers call for major reforms of the UN Sustainable Development Goals: SDG Summit a decisive moment

Researchers call for major reforms of the UN Sustainable Development Goals: SDG Summit a decisive moment
On 18-19 September, the United Nations will convene a major summit to review the state of the Sustainable Development Goals (SDGs)—the 17 global goals that governments agreed upon in 2015 to guide action towards a prosperous and just future. With research showing that the SDGs have since then had little political impact, the UN Summit must pave the way for four major changes in how the SDGs are implemented and governed globally, argues an international group of experts in Science. The article, based on research led by Utrecht University in the Netherlands, brought together a group of scholars with broad expertise in global sustainability governance. “Our ...

Researchers discover tissue-specific protection against protein aggregation

Researchers discover tissue-specific protection against protein aggregation
Key points:  Protein aggregation in certain tissues is a hallmark of diseases such as neurodegeneration and occurs during ageing, but little is known about how protein quality control mechanisms acting to prevent toxic protein build-up vary on a tissue-by-tissue basis.  Dr Della David and her team have discovered a safety mechanism that acts to lower levels of protein aggregation in C. elegans pharyngeal muscles, but is not active in body-wall muscles.  This new mechanism was identified by comparing protein accumulation in different tissues in ageing nematode worms when ...

Genetically modified bacteria break down plastics in saltwater

Researchers have genetically engineered a marine microorganism to break down plastic in salt water. Specifically, the modified organism can break down polyethylene terephthalate (PET), a plastic used in everything from water bottles to clothing that is a significant contributor to microplastic pollution in oceans. “This is exciting because we need to address plastic pollution in marine environments,” says Nathan Crook, corresponding author of a paper on the work and an assistant professor of chemical and biomolecular engineering ...

Study explains why certain immunotherapies don’t always work as predicted

CAMBRIDGE, MA -- This block is broken or missing. You may be missing content or you might need to enable the original module. Cancer drugs known as checkpoint blockade inhibitors have proven effective for some cancer patients. These drugs work by taking the brakes off the body’s T cell response, stimulating those immune cells to destroy tumors. Some studies have shown that these drugs work better in patients whose tumors have a very large number of mutated proteins, which scientists believe is because those proteins offer plentiful ...

Growth of large operators threatens existence of grassroots coworking spaces, study warns

The growing number of large operators and developers opening coworking premises threatens to end the availability of grassroots community-oriented spaces designed to bring isolated workers together, a new study warns. These coworking communities were originally set up to create serendipitous encounters, knowledge-sharing opportunities, and social capital. But the increasing numbers of big companies running flexible offices means they are less likely to offer services matching these aims. Smaller operators see the incursion by large commercial real estate developers ...

Using topology, Brown researchers advance understanding of how cells organize themselves

PROVIDENCE, R.I. [Brown University] — The fact that humans and other living organisms can develop and grow from a single cell relies on a process called embryonic development. For healthy tissue to form, cells in the embryo have to organize themselves in the right way in the right place at the right time. When this process doesn’t go right, it can result in birth defects, impaired tissue regeneration or cancer. All of which makes understanding how different cell types organize into a complex tissue ...

A call for better energy system models to enable a decarbonized future

Energy system models fail to accurately represent energy storage and might recommend decarbonization strategies that make electric grids less reliable. Policy makers and utilities need robust energy system models to determine the best strategies to decarbonize the world’s electric grids. But most existing models were designed for grids operating more than a decade ago. Today’s grids are much different. New technologies such as solar power and grid energy storage are being rapidly deployed. To accommodate these and other technologies, utilities must run grids in completely new ways. Improvements are needed in energy system ...

Stretching the truth: New research reveals negative effects of exaggerative political statements

Justifying policies through unsubstantiated or slightly invalid arguments can have a significantly negative effect on the public opinion of politicians, according to new research from City, University of London. With increasing scrutiny on global government policies in a ‘post-truth’ era, and in the aftermath of the Covid-19 pandemic that polarised international responses and reactions to the virus, an increased focus has been placed on policymakers to justify their actions and validate reasons for taking decisions. Short of lying, this can often politicians “stretching arguments” – making invalid claims that are difficult to both prove and disprove. The study, ...

Aegis Consortium funds research aimed at reducing the threat of future pandemics

Aegis Consortium funds research aimed at reducing the threat of future pandemics
The Aegis Consortium, an initiative of the University of Arizona Health Sciences, awarded approximately $650,000 in seed funding to eight pilot research projects in the areas of pandemic control, prediction or preparedness; post-acute effects of pandemics on individuals and societies; and the resilience of built and natural environments. “As we explore the challenges of pandemics such as COVID-19, we will continue to expand our investigative reach with domestic and international research teams to provide a range ...


12.5, the 1st Impact Factor of COMMTR released!

Circadian clock impact on cluster headaches funded by $2.4M NIH grant for UTHealth Houston research

Study identifies first drug therapy for sleep apnea

How old is your bone marrow?

Boosting biodiversity without hurting local economies

ChatGPT is biased against resumes with credentials that imply a disability — but it can improve

Simple test for flu could improve diagnosis and surveillance

UT Health San Antonio researcher awarded five-year, $2.53 million NIH grant to study alcohol-assisted liver disease

Giving pre-med students hands-on clinical training

CAMH research suggests potential targets for prevention and early identification of psychotic disorders

Mapping the heart to prevent damage caused by a heart attack

Study challenges popular idea that Easter islanders committed ‘ecocide’

Chilling discovery: Study reveals evolution of human cold and menthol sensing protein, offering hope for future non-addictive pain therapies.

Elena Beccalli, new rector of Università Cattolica del Sacro Cuore, takes office on 1st July

Pacific Northwest Research Institute uncovers hidden DNA mechanisms of rare genetic diseases

Empowering older adults: Wearable tech made easier with personalized support

Pennington Biomedical researchers partner on award-winning Long Covid study

Cooling ‘blood oranges’ could make them even healthier – a bonus for consumers

Body image and overall health found important to the sexual health of older gay men, according to new studies

Lab-grown muscles reveal mysteries of rare muscle diseases

Primary hepatic angiosarcoma: Treatment options for a rare tumor

Research finds causal evidence tying cerebral small-vessel disease to Alzheimer’s, dementia

Navigating the Pyrocene: Recent Cell Press papers on managing fire risk

Restoring the Great Salt Lake would have environmental justice as well as ecological benefits

Cannabis, tobacco use, and COVID-19 outcomes

A 5:2 intermittent fasting meal replacement diet and glycemic control for adults with diabetes

Scientists document self-propelling oxygen decline in the oceans

Activating molecular target reverses multiple hallmarks of aging

Cannabis use tied to increased risk of severe COVID-19

How to make ageing a ‘fairer game’ for all wormkind

[] Switching off the cytokine storm
EMBL Grenoble and University of Geneva researchers shed light on the molecular activation of the MAP kinase p38α, the final ‘switch’ triggering the inflammatory response