{"id":62543,"date":"2023-09-15T08:22:04","date_gmt":"2023-09-15T06:22:04","guid":{"rendered":"https:\/\/www.embl.org\/news\/?p=62543"},"modified":"2024-03-22T11:43:47","modified_gmt":"2024-03-22T10:43:47","slug":"switching-off-the-cytokine-storm","status":"publish","type":"post","link":"https:\/\/www.embl.org\/news\/science\/switching-off-the-cytokine-storm\/","title":{"rendered":"Switching off the cytokine storm"},"content":{"rendered":"\n<article class=\"vf-card vf-card--brand vf-card--bordered vf-u-margin__bottom--800\" default>\n  <div class=\"vf-card__content | vf-stack vf-stack--400\">\n      <h3 class=\"vf-card__heading\">\n      Summary    <\/h3>\n                <p class=\"vf-card__text\"><ul>\r\n \t<li>Inflammation is a normal response of our cells to fight stress, but too much of it during an infection can lead to a \u2018cytokine storm\u2019 that can endanger life.<\/li>\r\n \t<li>The inflammatory response is initiated by a cascade of kinases, like a series of successive switches. These enzymes have been heavily studied, but little is known about their interactions, making it difficult to develop efficient drugs to target them.<\/li>\r\n \t<li>EMBL Grenoble and University of Geneva researchers have gained insight into how the MAP kinase p38\u03b1, the final switch regulating inflammation, is activated by its upstream kinase.<\/li>\r\n \t<li>These results open up new directions to stop cytokine storms by targeting p38\u03b1 and to study similar processes in two other families of MAP kinases, implicated in Alzheimer&#8217;s disease and cancer, respectively.<\/li>\r\n<\/ul><\/p>\n      <\/div>\n<\/article>\n\n\n\n\n\n\n\n\n<p>Constant exposure of cells to stressing agents, such as pathogens, may disturb an organism\u2019s normal functioning. To fight stress, cells have developed several coping mechanisms, including the inflammatory response.&nbsp;<\/p>\n\n\n\n<p>While inflammation is necessary, too much of it can impair cell and organ function. This is the case with cytokine storms \u2013 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.<\/p>\n\n\n\n<p>In a <a href=\"https:\/\/www.science.org\/doi\/10.1126\/science.add7859\" target=\"_blank\" rel=\"noreferrer noopener\">new paper<\/a> published in <em>Science<\/em>, EMBL Grenoble and University of Geneva researchers provide essential insights on a protein called p38\u03b1, belonging to the Mitogen Activated Protein Kinase (MAPK) family, which is an important cellular \u2018switch\u2019 triggering the inflammatory response. They have obtained the first structure of p38\u03b1 being activated by another regulatory protein kinase \u2013 MKK6 \u2013 opening up new directions to develop drugs to stop cytokine storms.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>The final switch: a drug target<\/strong><\/h2>\n\n\n\n<p>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 \u2018switch\u2019 to transmit signals and activate gene expression. They do so by phosphorylation \u2013 adding a chemical group, phosphate, to other molecules to modulate their function.<\/p>\n\n\n\n<p>Bowler\u2019s 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.<\/p>\n\n\n\n<p>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 p38\u03b1 \u2013 the meeting point where all the signals converge and the last switch of the inflammatory process.<\/p>\n\n\n\n<p>Because the kinase chain reaction can come from different \u2018branches\u2019 of the logic circuit, this last switch is a particularly relevant drug target. The inflammatory response is regulated by p38\u03b1 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.<\/p>\n\n\n\n<p>Protein kinases, including p38\u03b1, have therefore been heavily studied. The first protein kinase structure was solved 30 years ago \u2013 a landmark in the field \u2013 and many more structures have followed, with over 7,000 structures now available in the Protein Data Bank.<\/p>\n\n\n\n<p>However, important parts of the puzzles are still missing. \u201cStructural biologists have obtained detailed information on the structure and functions of protein kinases, but mostly in isolation. So we don\u2019t really know how these enzymes are activated along the chain reaction,\u201d explained Bowler.<\/p>\n\n\n\n<p>Without this essential information about how the activation is triggered, drugs have mostly targeted the kinases\u2019 nucleotide-binding site \u2013 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.<\/p>\n\n\n\n<p>\u201cThere are many molecules that have been designed to target p38\u03b1, especially its nucleotide-binding site, but none have yet made it past clinical trials due to this lack of specificity,\u201d added Bowler.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\"><strong>Cracking the activation mechanism<\/strong><\/h2>\n\n\n\n<p>Bowler and a former PhD student in his lab, Erika Pellegrini, have therefore been investigating the interactions between p38\u03b1 and MKK6 &#8211; the kinase which activates it &#8211; since 2009.&nbsp; But studying the interaction between kinases proves to be extremely complex. \u201cThese enzymes are very dynamic molecules; they transmit important signals and need to act quickly. In the case of p38\u03b1, it has to go into the nucleus and activate lots of other different proteins,\u201d said Bowler.<\/p>\n\n\n\n<p>They were hampered by the fact that the interactions of the MKK6-p38\u03b1 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.<\/p>\n\n\n\n<p>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 \u2013 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.<\/p>\n\n\n\n<p>Tenacity and collaboration were key contributors to project success. &#8220;There were a lot of ups and downs, but there were always inspiring people or moments \u2013 one of these being particularly memorable,\u201d remembered Juyoux. \u201cWe obtained the first low-resolution 3D negative stain model on the exact same day that the <a href=\"https:\/\/www.embl.org\/news\/science\/jacques-dubochet-awarded-nobel-prize-for-chemistry\/\" target=\"_blank\" rel=\"noreferrer noopener\">Nobel Prize was announced for cryo-EM<\/a> in 2017. It gave us a boost of motivation!\u201d<\/p>\n\n\n\n<p>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 \u2013 crucial information for understanding how p38\u03b1 is activated. \u201cThis could be an interesting target for inhibitors that block this specific interaction, and consequently the signal triggering the inflammatory response,\u201d explained Juyoux.<\/p>\n\n\n\n<p>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&nbsp;how the two kinases interact. \u201cThey 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,\u201d explained Juyoux. \u201cThey also classified the different types of conformations of the complex to show how they assemble.\u201d&nbsp;<\/p>\n\n\n\n<p>Crucially, by comparing these simulations with the SAXS data they were able to model how the two proteins interact prior to catalysis. \u201cThe beauty of combining the state-of-the-art simulations with SAXS and cryo-EM data through advanced statistical approaches is that we can \u2018see\u2019 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,\u201d explained Francesco Gervasio. \u201cThe simulations required several months of supercomputing time generously allocated by the Swiss National Supercomputing Centre,\u201d he continued, \u201cBut it was well worth it, given the relevance of the final results.\u201d<\/p>\n\n\n\n<figure class=\"vf-figure wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"1024\" height=\"622\" class=\"vf-figure__image\" src=\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2023\/09\/graphical-abstract-Pauline-1024x622.png\" alt=\"\" class=\"wp-image-62545\" srcset=\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2023\/09\/graphical-abstract-Pauline-1024x622.png 1024w, https:\/\/www.embl.org\/news\/wp-content\/uploads\/2023\/09\/graphical-abstract-Pauline-300x182.png 300w, https:\/\/www.embl.org\/news\/wp-content\/uploads\/2023\/09\/graphical-abstract-Pauline-768x466.png 768w, https:\/\/www.embl.org\/news\/wp-content\/uploads\/2023\/09\/graphical-abstract-Pauline.png 1900w\" sizes=\"auto, (max-width: 1024px) 100vw, 1024px\" \/><figcaption class=\"vf-figure__caption\">Graphical abstract illustrating MAP kinases p38\u03b1 and MKK interactions and conformation states. <br \/>Credit: Pauline Juyoux\/EMBL<\/figcaption><\/figure>\n\n\n\n<p>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 \u2013 which are involved in cancer \u2013 and JNK kinases \u2013 also involved in inflammation, especially in Alzheimer\u2019s disease.<\/p>\n\n\n\n<p>\u201cKinases are very similar to one another in terms of sequence and structure, but we don&#8217;t know how and why they respond or send a specific signal,\u201d said Juyoux, whose current research project as a postdoctoral fellow at Institut de Biologie Structurale in Grenoble focuses on JNK kinases. \u201cComparing these different families of kinases could help explain the specificity of interactions and lead the way to new therapeutic approaches.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"<p>EMBL Grenoble and University of Geneva researchers shed light on the molecular activation of the MAP kinase p38\u03b1, the final \u2018switch\u2019 triggering the inflammatory response.<\/p>\n","protected":false},"author":104,"featured_media":62551,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[2,17591],"tags":[17279,37,17277,411,35],"embl_taxonomy":[9792,19335],"class_list":["post-62543","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-science","category-science-technology","tag-cryo-electron-microscopy","tag-grenoble","tag-kinase","tag-mccarthy","tag-structural-biology","embl_taxonomy-embl-grenoble","embl_taxonomy-mccarthy-team"],"acf":{"featured":true,"show_featured_image":false,"field_target_display":"embl","field_article_language":{"value":"english","label":"English"},"article_intro":"<p>EMBL Grenoble and University of Geneva researchers shed light on the molecular activation of the MAP kinase p38\u03b1, the final \u2018switch\u2019 triggering the inflammatory response<\/p>\n","related_links":[{"link_description":"McCarthy team","link_url":"https:\/\/www.embl.org\/groups\/mccarthy\/"}],"source_article":[{"publication_title":"Architecture of the MKK6-p38\u03b1 complex defines the basis of MAPK specificity and activation","publication_link":{"title":"","url":"https:\/\/www.science.org\/doi\/10.1126\/science.add7859","target":"_blank"},"publication_authors":"Juyoux P., et al.","publication_source":"Science","publication_date":"14 September 2023","publication_doi":""}],"in_this_article":false,"press_contact":"None","article_translations":false,"languages":""},"embl_taxonomy_terms":[{"uuid":"a:3:{i:0;s:36:\"b14d3f13-5670-44fb-8970-e54dfd9c921a\";i:1;s:36:\"89e00fee-87f4-482e-a801-4c3548bb6a58\";i:2;s:36:\"8f81131e-d37c-470c-848f-618fce652295\";}","parents":[],"name":["EMBL Grenoble"],"slug":"embl-grenoble","description":"Where &gt; All EMBL sites &gt; EMBL Grenoble"},{"uuid":"a:3:{i:0;s:36:\"302cfdf7-365b-462a-be65-82c7b783ebf7\";i:1;s:36:\"fc528877-4017-438f-85b4-de2b54c443f1\";i:2;s:36:\"cace2fac-b6a0-45a4-aa9c-2ffce0858c05\";}","parents":[],"name":["McCarthy Team"],"slug":"mccarthy-team","description":"What &gt; Structural Biology (EMBL Grenoble) &gt; McCarthy Team"}],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.2 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Switching off the cytokine storm | EMBL<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.embl.org\/news\/science\/switching-off-the-cytokine-storm\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Switching off the cytokine storm | EMBL\" \/>\n<meta property=\"og:description\" content=\"EMBL Grenoble and University of 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from inflammatory cytokines activates several protein kinases in a chain \u2013 at the end of this process MKK6 (yellow) \u2018switches on\u2019 p38\u03b1 (green) by binding it and adding phosphates. The combination of computer simulations, SAXS, and cryo-EM has shown how the two proteins interact and bind to each other to transmit the signal. 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The combination of computer simulations, SAXS, and cryo-EM has shown how the two proteins interact and bind to each other to transmit the signal. Credits: Ella Marushchenko, Isabel Romero Calvo\/EMBL"},{"@type":"WebSite","@id":"https:\/\/www.embl.org\/news\/#website","url":"https:\/\/www.embl.org\/news\/","name":"European Molecular Biology Laboratory News","description":"News from the European Molecular Biology Laboratory","publisher":{"@id":"https:\/\/www.embl.org\/news\/#organization"},"alternateName":"EMBL News","potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/www.embl.org\/news\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"en-US"},{"@type":"Organization","@id":"https:\/\/www.embl.org\/news\/#organization","name":"European Molecular Biology Laboratory","alternateName":"EMBL","url":"https:\/\/www.embl.org\/news\/","logo":{"@type":"ImageObject","inLanguage":"en-US","@id":"https:\/\/www.embl.org\/news\/#\/schema\/logo\/image\/","url":"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2025\/09\/EMBL_logo_colour-1-300x144-1.png","contentUrl":"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2025\/09\/EMBL_logo_colour-1-300x144-1.png","width":300,"height":144,"caption":"European Molecular Biology Laboratory"},"image":{"@id":"https:\/\/www.embl.org\/news\/#\/schema\/logo\/image\/"},"sameAs":["https:\/\/www.facebook.com\/embl.org\/","https:\/\/x.com\/embl","https:\/\/www.instagram.com\/embl_org\/","https:\/\/www.linkedin.com\/company\/15813\/","https:\/\/www.youtube.com\/user\/emblmedia\/"]},{"@type":"Person","@id":"https:\/\/www.embl.org\/news\/#\/schema\/person\/845a38992ad0698d457ec1dd32d13c79","name":"Myl\u00e8ne Andr\u00e9","image":{"@type":"ImageObject","inLanguage":"en-US","@id":"https:\/\/www.embl.org\/news\/#\/schema\/person\/image\/","url":"https:\/\/secure.gravatar.com\/avatar\/9fde990ea593a68856d19cf7977a6cedcffea68f7171a1d49b0383e263032765?s=96&d=mm&r=g","contentUrl":"https:\/\/secure.gravatar.com\/avatar\/9fde990ea593a68856d19cf7977a6cedcffea68f7171a1d49b0383e263032765?s=96&d=mm&r=g","caption":"Myl\u00e8ne Andr\u00e9"},"url":"https:\/\/www.embl.org\/news\/author\/mandreembl-fr\/"}]}},"field_target_display":"embl","field_article_language":{"value":"english","label":"English"},"fimg_url":"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2023\/09\/kinase_p38_1000x600.jpg","featured_image_src":"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2023\/09\/kinase_p38_1000x600.jpg","_links":{"self":[{"href":"https:\/\/www.embl.org\/news\/wp-json\/wp\/v2\/posts\/62543","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.embl.org\/news\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.embl.org\/news\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.embl.org\/news\/wp-json\/wp\/v2\/users\/104"}],"replies":[{"embeddable":true,"href":"https:\/\/www.embl.org\/news\/wp-json\/wp\/v2\/comments?post=62543"}],"version-history":[{"count":28,"href":"https:\/\/www.embl.org\/news\/wp-json\/wp\/v2\/posts\/62543\/revisions"}],"predecessor-version":[{"id":67321,"href":"https:\/\/www.embl.org\/news\/wp-json\/wp\/v2\/posts\/62543\/revisions\/67321"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.embl.org\/news\/wp-json\/wp\/v2\/media\/62551"}],"wp:attachment":[{"href":"https:\/\/www.embl.org\/news\/wp-json\/wp\/v2\/media?parent=62543"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.embl.org\/news\/wp-json\/wp\/v2\/categories?post=62543"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.embl.org\/news\/wp-json\/wp\/v2\/tags?post=62543"},{"taxonomy":"embl_taxonomy","embeddable":true,"href":"https:\/\/www.embl.org\/news\/wp-json\/wp\/v2\/embl_taxonomy?post=62543"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}