Press releases – July 2023

Originally, the powerhouses of higher cells, the mitochondria, were independent organisms. Researchers at Goethe University Frankfurt have investigated to what extent their metabolism has blended with that of their host cells in the course of evolution, using the example of a mitochondrial stress response. They have discovered that mitochondria send two different biochemical signals. These are processed together in the cell and trigger a support mechanism to restore cellular balance (homeostasis). The work was partly done within the ENABLE cluster initiative (now EMTHERA) at Goethe University Frankfurt. 

As life propagated across Earth in the form of the widest variety of single-celled organisms, sometime between 3.5 and a billion years ago one such organism managed an evolutionary coup: Instead of devouring and digesting bacteria, it encapsulated its prey and used it as a source of energy. As a host cell, it offered protection and nutrition in return. This is referred to as the endosymbiotic theory, according to which that single-celled organism was the primordial mother of all higher cells, out of which all animals, fungi and plants developed. Over the course of billions of years, the encapsulated bacterium became the cell's powerhouse, the mitochondrion, which supplies it with the cellular energy currency ATP. It lost a large part of its genetic material – its DNA – and exchanged smaller DNA segments with the mother cell. However, now as in the past, mitochondria divide independently of the cell and possess some genes of their own. 

How closely the cell and the mitochondrion work together in human cells today is what a team of researchers led by Dr. Christian Münch of Goethe University Frankfurt is investigating. They have now discovered how the mitochondrion calls for help from the cell when it is under stress. Triggers for such stress can be infections, inflammatory diseases or genetic disorders, for example, but also nutrient deficiencies or cell toxins. 

A certain type of mitochondrial stress is caused by misfolded proteins that are not quickly degraded and accumulate in the mitochondrion. The consequences for both the mitochondrion and the cell are dramatic: Misfolded proteins can, for example, disrupt energy production or lead to the formation of larger amounts of reactive oxygen compounds, which attack the mitochondrial DNA and generate further misfolded proteins. In addition, misfolded proteins can destabilize the mitochondrial membranes, releasing signal substances from the mitochondrion that activate apoptosis, the cell's self-destruction program. 

The mitochondrion responds to the stress by producing more chaperones (folding assistants) to fold the proteins in order to reduce the misfolding, as well as protein shredding units that degrade the misfolded proteins. Until now, how cells trigger this protective mechanism was unknown. 

The researchers from Goethe University Frankfurt artificially triggered misfolding stress in the mitochondria of cultured human cells and analyzed the result. “What makes it difficult to unravel such signaling processes," explains Münch, himself a biochemist, “is that an incredibly large number take place simultaneously and at high speed in the cell." The research team therefore availed itself of methods (transcriptome analyses) that can be used to measure over time to what extent genes are transcribed. In addition, the researchers observed, among other things, which proteins bind to each other at which point in time, at which intervals the concentrations of intracellular substances change, and what effects there are when individual proteins are systematically deactivated. 

The result is that the mitochondria send two chemical signals to the cell when protein misfolding stress occurs: They release reactive oxygen compounds and block the import of protein precursors, which are produced in the cell and are only folded into their functional shape inside the mitochondrion, causing these precursors to accumulate in the cell. Among other things, the reactive oxygen compounds lead to chemical changes in a protein called DNAJA1. Normally, DNAJA1 supports a specific chaperone (folding assistant) in the cell, which molds the cell's newly formed proteins into the correct shape. 

As a consequence of the chemical change, DNAJA1 now increasingly forces itself on the folding assistant HSP70 as its helper. HSP70 then takes special care of the misfolded protein precursors that accumulate around the mitochondrion because of the blocked protein import. By doing so, HSP70 reduces its interaction with its regular partner HSF1. HSF1 is now released and can migrate into the cell nucleus, where it can trigger the anti-stress mechanism for the mitochondrion. 

As biochemist Münch explains, “It was very exciting to discover how the two mitochondrial stress signals are combined into one signal in the cell, which then triggers the cell's response to mitochondrial stress. Moreover, in this complex process, which is essentially driven by tiny local changes in concentration, the stress signaling pathways of the cell and the mitochondrion dovetail very elegantly with each other – like the cogs in a clockwork." 

Publication: F. X. Reymond Sutandy, Ines Gößner, Georg Tascher, Christian Münch: A cytosolic surveillance mechanism activates the mitochondrial UPR. Nature (2023) https://doi.org/10.1038/s41586-023-06142-0 

Background information:
Misfolding in mitochondria: Emmy Noether grant of the German Research Foundation for Christian Münch
https://aktuelles.uni-frankfurt.de/english/misfolding-in-mitochondria-how-does-the-cell-react/?highlight=M%C3%BCnch 

The EMTHERA (Emerging Therapies) research cluster is seeking new approaches to study infections and inflammatory diseases as well as immune system disorders and to develop innovative therapies. EMTHERA is an initiative of the Rhine-Main Universities (RMU). https://www.emthera.de/ 

Picture download: http://www.uni-frankfurt.de/93374838 

Caption: Dr. Christian Münch, Institute of Biochemistry II, Goethe University Frankfurt. Photo: Uwe Dettmar for Goethe University 

Further information:
Dr. Christian Münch
Emmy Noether Group Leader – Protein Quality Control & Quantitative Proteomics
Institute of Biochemistry II
Faculty of Medicine
Goethe University Frankfurt
Tel.: +49 (0)69 6301-3715
Web: https://pqc.biochem2.de
Twitter: @MuenchLab @goetheuni

Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Tel: +49 (0) 69 798-12498, Fax: +49 (0) 69 798-763 12531, bernards@em.uni-frankfurt.de.

The intellectual and artistic activities of Jews in Nazi Germany are the focus of a new joint doctoral program run by Goethe University Frankfurt, Europa-Universität Viadrina Frankfurt (Oder), and the University of Music Franz Liszt in Weimar. 

The Hans Böckler Foundation is providing around €900,000 in funding for the interdisciplinary doctoral program "Broken Traditions? Jewish Literature, Philosophy and Music in Nazi Germany," jointly funded by the Europa-Universität Viadrina Frankfurt (Oder), Goethe University Frankfurt, and the University of Music Franz Liszt in Weimar. The funding was initially approved for 4.5 years. 

From the 2024 summer semester onwards, nine doctoral students at all three universities will scientifically study the intellectual and artistic activities of Jews that were mediated, openly articulated, or illegally disseminated within Nazi Germany in response to the social disenfranchisement, exclusion, and ultimately the murder of large sections of European Jewry. 

The PhDs will be supervised by Prof. Kerstin Schoor (German-Jewish Literary and Cultural History, Exile and Migration, Europa-Universität Viadrina Frankfurt (Oder)), Prof. Christian Wiese (Martin Buber Professorship for Jewish Philosophy of Religion, Goethe University Frankfurt), and Prof. Jascha Nemtsov (History of Jewish Music, University of Music Franz Liszt Weimar). The doctoral program will be based at the Selma Stern Center for Jewish Studies Berlin-Brandenburg. 

The program's cooperation partners are the Yad Vashem World Holocaust Remembrance Center's International Institute for Holocaust Research, the Hebrew University of Jerusalem's Franz Rosenzweig Minerva Research Center, the Leo Baeck Institute Jerusalem, and the Music Department of Haifa University's Dr. Hecht Arts Center. 

Scholarships will be announced at the end of August 2023. Interested applicants should contact their desired primary supervisor during September 2023, preferably no later than September 15. Scholarship applications will be considered in consultation with the Hans Böckler Foundation, and should be submitted by November 2, 2023. 

The joint doctoral program in their words 

"I am very pleased that this funding from the Hans Böckler Foundation will allow a specific thematic focus of the participating chairs and institutions to be deepened in an interdisciplinary collaborative project, and passed on to a new generation of scholars," says Prof. Dr. Kerstin Schoor, who, in addition to being the spokesperson of the new doctoral program, also serves as Chair of German-Jewish Literary and Cultural History, Exile and Migration at Europa-Universität Viadrina Frankfurt (Oder). 

"Exploring the doctoral program's thematic field from the perspective of the three participating disciplines promises not only insights into the past, but also informed discussions about the pressing challenges of our time – something I look forward to," says Prof. Dr. Christian Wiese, Director of the Frankfurt Buber-Rosenzweig Institute in Frankfurt. 

In the same spirit, Prof. Dr. Jascha Nemtsov (Weimar) also welcomes the program as "a great opportunity to research the work of Jewish composers in Nazi Germany and to give their works back to contemporary musical life." 

The Hans Böckler Foundation "is pleased to be able to support nine dissertations on Jewish literature, philosophy and music in Nazi Germany in an interdisciplinary research context in its new doctoral college (PK057)." It is supporting the program's first funding phase with institutional and individual funding of around €900,000. 

Background: 

Forced by political censorship and a massive process of exclusion and persecution of Jews in Nazi Germany that began as early as 1933, the developments in literature, philosophy, and music at the time were characterized more strongly than in other periods by a (critical) reflection on traditional artistic-aesthetic, cultural, and religious traditions. For intellectuals, writers, and musicians of Jewish origin, the relationship to traditions of German, Jewish and European cultures became a crucial question of intellectual and artistic-aesthetic formation. 

The program aims to expand the knowledge of Jewish cultural life in the increasingly separated Jewish cultural circle within Nazi Germany that emerged after 1933 in literary, philosophy and religious studies, as well as musicology. Framed by the common research question “Broken traditions?", intellectual, literary and artistic-aesthetic references to tradition in the cultural life of German Jews of 1930s and early 1940s Nazi Germany will be subject to a critical re-reading. 

In so doing, the doctoral program constitutes a response to a state of research that – in contrast to historiography – remains characterized by a widespread lack of representation of characteristic developments in the literature, philosophy, and music of Jewish intellectuals and artists in Nazi Germany, as well as a widespread lack of reflection on the reasons for the delayed history of reception of these intellectual and artistic activities, from the postwar years until the 1990s. In addition, and in a way that varies from discipline to discipline, the prevailing state of research was and in part still is characterized by a desolate source situation. The program thus constitutes part of the international efforts of Nazi and Holocaust research, within the framework of which it also lays claim to originality in its specific disciplinary composition as well as its content. 

Further information: 
Prof. Dr. Christian Wiese, c.wiese@em.uni-frankfurt.de
Martin Buber Professorship for Jewish Philosophy of Religion and Buber-Rosenzweig Institute for Jewish Intellectual and Cultural History of Modernity at Goethe University Frankfurt

Prof. Dr. Kerstin Schoor, schoor@europa-uni.de
Axel Springer Chair for German-Jewish Literary and Cultural History, Exile and Migration at Europa-Universität Viadrina Frankfurt (Oder) 

Prof. Dr. Jascha Nemtsov, jascha.nemtsov@hfm-weimar.de
Chair for the History of Jewish Music at the University of Music Franz Liszt in Weimar

Editor: Dr. Anke Sauter, Science Editor, PR & Communication Office, Tel: +49 (0)69 798-13066, Fax: +49 (0) 69 798-763 12531, sauter@pvw.uni-frankfurt.de

Like carbon dioxide, many gaseous substances containing halogens such as chlorine or fluorine contribute to the greenhouse effect. Researchers from Goethe University Frankfurt have now put a measuring device into operation at the Taunus Observatory on Kleiner Feldberg, a mountain near Frankfurt, which continuously monitors the concentrations of such gases with very high accuracy for the first time in Germany and within an international network. Initial results indicate that sources of special fluorinated gases (F-gases) are present in Germany as well. The scientists in Frankfurt emphasize that recording F-gases ought to be included in the official air monitoring program in the long term. 

In the past, they were found in every refrigerator and aerosol until it was discovered that they had ripped a hole in the ozone layer protecting Earth's atmosphere: chlorofluorocarbons, in short CFCs. Since 2000, the Montreal Protocol has practically abolished CFC production worldwide. Halogenated hydrocarbons without chlorine, known as F-gases, were increasingly used as a substitute – until it emerged that these gases, although they do not constitute a threat to the ozone layer, are nonetheless potent greenhouse gases, just like CFCs. Accordingly, F-gases were added to the Montreal Protocol in 2016 within the “Kigali Amendment". In Europe, the F-Gas Regulation (517/2014) aims to ensure the reduction of emissions. 

Despite their low concentrations, halogenated greenhouse gases play a significant role in climate change: They are responsible for up to nine percent of the anthropogenic greenhouse effect – one kilogram of these gases can have the same impact on the climate as ten tons of carbon dioxide. To date, however, their occurrence in the atmosphere has not been systematically monitored in Germany. 

Within the ACTRIS research infrastructure, scientists from Goethe University Frankfurt have now put a measuring device called “Medusa" into operation at the Taunus Observatory on Kleiner Feldberg, a mountain near Frankfurt, which continuously measures the concentration of many trace gases relevant for the atmosphere. Their measurements of halogenated greenhouse gases are also incorporated in the international AGAGE network, which has been monitoring the occurrence of climate-relevant trace gases at stations all over the world since 1978. These are the first high-quality measurements of this kind in Germany that can also be compared with data worldwide.

Professor Andreas Engel from the Institute for Atmospheric and Environmental Sciences at Goethe University Frankfurt, who is in charge of “Medusa", says: “Our measurements have already clearly shown that there are significant sources of F-gases in Germany. We have therefore joined forces within an EU-funded project with other researchers, primarily from Germany, Switzerland and the UK, to quantify F-gas emissions on the basis of these measurements with the help of computer models and to further narrow down their regions of origin." 

The very low concentrations, the large number of components to be measured and the high accuracies required make the measurements very complex, he says. He is convinced, however, that – because of their significance – measuring F-gases should shift from research to official air monitoring in the long term: “We need to set up a program that also integrates the systematic recording of halogenated greenhouse gases, including F-gases, into the official atmospheric measurement system. This could deliver sufficient data to identify sources and take appropriate countermeasures." 

Background:
Greenhouse gases thought dead (Forschung Frankfurt 2-2020)
https://www.forschung-frankfurt.uni-frankfurt.de/108794305.pdf 

AGAGE: Advanced Global Atmospheric Gases Experiment
https://agage.mit.edu/ 

Picture download: https://www.uni-frankfurt.de/140750923 

Caption: The Taunus Observatory on the mountain Kleiner Feldberg near Frankfurt am Main houses the new "Medusa" device, which detects climate-relevant F-gases. Photo: Markus Bernards, Goethe University 

Further information
Professor Andreas Engel
Institute for Atmospheric and Environmental Sciences
Goethe University Frankfurt
Tel.: + 49 (0)69 798-40259
an.engel@iau.uni-frankfurt.de
Website: http://www.geo.uni-frankfurt.de/iau
Twitter: @goetheuni

Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Tel: +49 (0) 69 798-12498, Fax: +49 (0) 69 798-763 12531, bernards@em.uni-frankfurt.de.

In all living organisms, the biomolecule transfer RNA (tRNA) plays a fundamental role in protein production. tRNAs are generated from precursor molecules in several steps. The enzyme tRNA splicing endonuclease (TSEN), among other things, catalyzes one step in this process. Mutations in TSEN lead to a neurodegenerative disorder called pontocerebellar hypoplasia, which is associated with severe disabilities and early death. Researchers at Goethe University Frankfurt and at Johannes Gutenberg University Mainz have now deduced the function of TSEN from its structure and in so doing paved the way in the search for active substances against pontocerebellar hypoplasia. 

Transfer RNAs (tRNAs) are among the most common types of RNA in a cell and are indispensable for protein production in all known organisms. They have an important “translation" function: They determine how the sequence of nucleic acids, in which the genetic information is encoded, is transcribed into a sequence of amino acids from which proteins are built. 

Transfer RNAs are generated from precursor tRNAs (pre-tRNAs), which are converted in several steps into the mature tRNA with a complex three-dimensional structure. In some tRNAs, this includes a step in which a certain section, known as an intron, is excised. In humans, the tRNA splicing endonuclease (TSEN) performs this task. 

The enzyme RNA kinase CLP1, which binds directly to TSEN, also plays a role in ensuring the correct conversion of tRNAs. If TSEN and CLP1 are unable to interact with each other due to a genetic mutation, it seems that tRNAs can no longer form correctly either. The consequences of this are often seen in the development of neurodegenerative disorders. One of these is pontocerebellar hypoplasia, which leads to severe disabilities and premature death in earliest childhood. This very rare progressive disorder manifests itself in an abnormal development of the cerebellum and the pons, a part of the brain stem. 

Although TSEN activity is essential for life, it was to date mostly unclear how the enzyme binds pre-tRNAs and how introns are excised. The lack of a three-dimensional structure of the enzyme also made it difficult to assess the changes triggered by specific pathogenic mutations. By means of cryo-electron microscopy (cryo-EM) conducted at facilities of the Julius-Maximilians University of Würzburg and of the Institute of Biochemistry at Goethe University Frankfurt, researchers led by Dr. Simon Trowitzsch from the Institute of Biochemistry at Goethe University have now succeeded in shedding light on the three-dimensional structure of a TSEN/pre-tRNA complex. 

With the aid of their cryo-EM reconstructions, the research team was able to show for the first time how TSEN interacts with the L-shaped pre-tRNA. TSEN then excises the intron from the long arm of the L. “First, TSEN settles in the corner of the L. It can then recognize both the short and the long arm as well as the angle between them," explains Trowitzsch. 

The TSEN subunit 54 (TSEN54) plays a key role in pre-tRNA recognition, as the researchers have now been able to corroborate. The subunit serves as a “molecular ruler" and measures the distance between the long and the short arm of the L. In this way, TSEN recognizes at which point the pre-tRNA needs to be cleaved in order to remove the intron. 

New findings on the interaction of the RNA kinase CLP1 and the TSEN subunit TSEN54 were a surprise: CLP1 evidently binds to an unstructured and thus very flexible region of TSEN54. It is precisely this region that contains an amino acid most frequently mutated in patients with pontocerebellar hypoplasia. “For us, this is an important indication that drug development in the future should concentrate on maintaining the interaction of TSEN and CLP1," Samoil Sekulovski, first author of the study, is convinced. 

The scientists now hope that the structural data will make it possible to simulate models that can be used to search for potential active substances. Trowitzsch sums up: “Although a promising therapy is still a long way ahead of us, our structure indeed forms a solid foundation for a better understanding of how TSEN works and what the disease patterns of its mutants are." 

Publication: Samoil Sekulovski, Lukas Sušac, Lukas S. Stelzl, Robert Tampé, Simon Trowitzsch: Structural basis of substrate recognition by human tRNA splicing endonuclease TSEN. Nature Structural & Molecular Biology (2023) https://doi.org/10.1038/s41594-023-00992-y 

News&Views: Anita K. Hopper & Jinwei Zhang: Captured: the elusive eukaryotic tRNA splicing enzyme. Nature Structural & Molecular Biology (2023) https://doi.org/10.1038/s41594-023-00995-9 

Picture download: https://www.uni-frankfurt.de/140143743 

Caption: Trimmed: Like scissors, the enzyme TSEN shapes tRNA (colored) by removing parts of the precursor molecule pre-tRNA. Image: Trowitzsch Lab, Goethe University 

Further information
Dr. Simon Trowitzsch
Institute of Biochemistry, Biocenter
Goethe University Frankfurt
Tel.: +49 (0) 69 798 29 273
trowitzsch@biochem.uni-frankfurt.de
Website: https://www.biochem.uni-frankfurt.de/index.php?id=256

Editor: Markus Bernards, PhD, Science Editor, PR & Communication Office, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Tel: +49 (0) 69 798-12498, Fax: +49 (0) 69 798-763 12531, bernards@em.uni-frankfurt.de

As part of the immune system, dendritic cells are essential for fighting body cells that have degenerated or are infected with a virus. They trigger an immune response by presenting protein fragments, for example of viruses, to T cells. In so doing, they activate the latter so that these recognize the fragments as foreign. Certain membrane proteins, MHC-I molecules, enable this process within dendritic cells. Researchers at Goethe University Frankfurt and its partner institutes have now identified further interaction partners of the protein complex responsible for loading MHC-I molecules in dendritic cells. 

The specific or acquired immune system of vertebrates is a powerful weapon against pathogens and pathologically altered body cells. Here, T cells play a special role. After activation, they can systematically kill off target cells that have degenerated or are infected with a virus. They carry a receptor on their surface that recognizes small protein fragments – antigens – presented to them by specialized immune cells, including the highly efficient dendritic cells. These are phagocytes (scavenger cells) that patrol through the body in search of infected or degenerated cells, ingest them and degrade them inside a membrane vesicle. During this process, antigens are produced that enable the dendritic cells to bind to MHC-I receptors and then present them on the cell surface. 

The antigenic MHC-I molecules remain stable for several days. During this time, their purpose is to activate immature (naïve) T cells and transform them into potent killer cells (cytotoxic T cells). Thanks to this “armoring function", dendritic cells constitute a ray of hope for personalized immunotherapy. With the participation of Dr. Christian Schölz from the Max von Pettenkofer Institute in Munich as well as Professor Reinhold Förster and Professor Ulrich Kalinke from Hannover Medical School, a team led by Professor Robert Tampé from Goethe University Frankfurt has now been able to show that the protein complex responsible for loading MHC-I molecules in dendritic cells is organized in supramolecular assemblies for particularly efficient antigen presentation. 

Like all surface proteins, MHC-I molecules are incorporated into the membrane of the intracellular endoplasmic reticulum (ER) during synthesis. The ER is a system of tubules and sacs inside the cell, in which the MHC-I molecules are loaded with antigens carried there via a transporter called TAP. 

Small vesicles with the loaded MHC-I molecules bud off from the endoplasmic reticulum, migrate to the cell membrane and fuse with it so that they appear on the cell surface and can interact with T cells. “All body cells with a nucleus present their own antigens to the immune system," Tampé explains, “but dendritic cells are the ones that present the antigens of other cells on MHC-I best of all and in this way are able to arm T cells." This is because dendritic cells have an ER with a particularly extensive network of tubules and sacs. 

For their experiments, the researchers examined dendritic cells in an early stage of cell development, known as progenitor cells, allowing them to develop first into immature and then mature dendritic cells. In all three groups of cells, they found an antigenic peptide loading complex composed of TAP, MHC-I and three other proteins: tapasin, ERp57 and calreticulin, folding enzymes (chaperones) that help the three-dimensional structure of MHC-I to form correctly. 

In the mature dendritic cells, three other proteins further enriched the loading complex: The researchers discovered VAPA and ESYT1 in close proximity, which normally appear at contact sites between the ER and other cell membranes, as well as BAP31. BAP31 occurs at ER exit sites, that is, where the vesicles with the folded proteins bud off from the ER. “This result indicates that antigen processing in dendritic cells is more efficient when the loading complex does not operate on its own but works in organized alliances," says Martina Barends, one of the first authors of the research paper. 

This cooperation with the newly described partners suggests that loading of MHC-I molecules occurs at ER exit sites, which could enable the complexes to reach the cell surface particularly quickly. Moreover, loading complexes at contact sites between the ER and plasma membrane could facilitate direct transport to the cell surface. Tampé is convinced: “This would make antigen presentation far more efficient." The hope now is that these findings will help in the development of new immunization strategies and immunotherapies. “We now have a better idea of how antigens are produced in dendritic cells that can be used therapeutically," summarizes Tampé. 

Publication: Martina Barends, Nicole Koller, Christian Schölz, Verónica Durán, Berislav Bosnjak, Jennifer Becker, Marius Döring, Hanna Blees, Reinhold Förster, Ulrich Kalinke, Robert Tampé: Dynamic interactome of the MHC I peptide loading complex in human dendritic cells. PNAS (2023) https://doi.org/10.1073/pnas.2219790120 

Further information:
Professor Robert Tampé
CRC 1507 – Protein Assemblies and Machineries in Cell Membranes (https:/sfb1507.de)
Institute for Biochemistry, Biocenter
Goethe University Frankfurt, Germany
Tel.: +49 69 798-29475
tampe@em.uni-frankfurt.de
Website: https://www.biochem.uni-frankfurt.de/index.php?id=10
CRC 1507: https://sfb1507.de

Editor: Dr. Markus Bernards, Science Editor, PR & Communication Office, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Tel: +49 (0) 69 798-12498, Fax: +49 (0) 69 798-763 12531, bernards@em.uni-frankfurt.de.