A novel ubiquitination mechanism explains pathogenic effects of Legionella infection
FRANKFURT. The attachment of ubiquitin was long considered as giving the „kiss of death“, labelling superfluous proteins for disposal within a cell. However, by now it has been well established that ubiquitin fulfils numerous additional duties in cellular signal transduction. A team of scientists under the lead of Ivan Dikic, Director of the Institute of Biochemistry II at Goethe University Frankfurt, has now discovered a novel mechanism of ubiquitination, by which Legionella bacteria can seize control over their host cells. Legionella causes deadly pneumonia in immunocompromised patients.
According to the current understanding, the coordinated action of three enzymes is needed for attaching ubiquitin to other proteins. In April this year, U.S. scientists described an ubiquitination reaction that depends only on a single enzyme from Legionella bacteria. The Dikic team together with the group of Ivan Matic (Max Planck Institute for Biology of Ageing, Cologne, Germany) now elucidated the underlying molecular mechanism of its action and revealed a hitherto unknown type of chemical linkage between ubiquitin and target proteins.
Their discovery breaks new ground in the field. Sagar Bhogaraju, researcher in the Dikic laboratory, comments: “Most exciting is of course the question if this unusual ubiquitination also occurs in human cells independently of bacterial infection and if there are similar, so far unknown enzymes in humans, which may have a profound influence on cellular processes.”
When studying the new mechanism in more detail, the Frankfurt scientists were very surprised to find that the Legionella enzyme does not only transfer ubiquitin onto target proteins, but also chemically manipulates the remaining pool of ubiquitin molecules. Modified ubiquitin almost completely inhibits the conventional ubiquitination system, thereby revealing a new role for this enzyme during Legionella infections.
Several important cellular processes are affected by this shut-down of the ubiquitination system, which can also cause a rapid cell death. The Dikic team showed for example that modified ubiquitin prevents degradation of mitochondria (a process called mitophagy), affects transduction of inflammatory signals and constrains protein degradation.
“Most likely, Legionella is not the only bacterium using this mechanism. We hope that our results help to identify new strategies for the development of antibacterial agents, which could complement conventional antibiotics by limiting cellular damage induced by bacterial enzymes”, explains Dikic the high medical relevance of their discovery.
The group of Ivan Dikic is located at both the Institute of Biochemistry II and the Buchmann Institute for Molecular Life Sciences at Goethe University Frankfurt and has previously contributed significantly to a paradigm change in the ubiquitin field. Ivan hypothesized early on that ubiquitin signals are recognized and translated by specialized domains in other proteins. He identified ubiquitin-binding domains in more than 200 ubiquitin receptors and was able to prove their role in diseases like cancer, amyotrophic lateral sclerosis and Parkinson’s.
Publication: Bhogaraju S, Kalayil S, Liu Y, Bonn F, Colby T, Matic I, Dikic I. Phosphoribosylation of ubiquitin promotes serine ubiquitination and impairs conventional ubiquitination. Cell. 2016 Dec;167(6). DOI10.1016/j.cell.2016.11.019
Information: Dr. Kerstin Koch, Institute of Biochemistry II, University Hospital Frankfurt, Phone: +49 69 6301 84250, firstname.lastname@example.org
Study by PwC and Goethe University Frankfurt reveals: In Dax and MDax-listed companies, bonuses are decoupled from corporate success after payout
Frankfurt. To date, the bonuses paid out to executive board members in Germany have not been sufficiently linked to long-term corporate success. This is the conclusion reached in the new “Remuneration Report” by consultants PwC in cooperation with Goethe University Frankfurt. Whilst about 60 percent of overall remuneration for Dax and MDax board members is indeed made up of performance-related payments – of which in turn more than half are long-term – most of these payments, which are known as Long Term Incentives (LTIs), are in cash rather than based on share plans. That means: Bonuses are automatically decoupled from business development the moment they are paid out.
“When compared at international level, Germany can thus be classed as a special case. In our view, it would be more advantageous if long-term bonuses were awarded in the shape of shares in the respective company and the board members were also bound by means of corresponding clauses actually to keep these securities for a longer period of time, if necessary even beyond their term of office. This would ensure that it is in board members’ vested interest really to work towards the company’s long-term success”, says Remo Schmid, co-author of the report and partner at PwC in Germany responsible for remuneration issues.
CEOs earn almost twice as much as their board colleagues
For the report, PwC and Goethe University Frankfurt examined remuneration structures in Dax and MDax companies. The analysis shows that developments in executive board remuneration in 2015 differed in comparison to the previous year: On average, a Dax CEO earned € 5.6 million, a plus of a good 3 percent. Other board members earned € 2.9 million, which equates to a minus of 2 percent. CEOs in MDax companies earned € 2.5 million on average, whilst their board colleagues were paid € 1.3 million. In other words: On the Dax, the barometer for blue chip companies, top managers are paid more than twice as much as their counterparts in medium-sized enterprises on the MDax. What’s more: The average CEO earns on average almost double the salary of a “normal” board member.
Women are still greatly underrepresented
According to the analysis, the percentage of women amongst top-level executives is rising at an astoundingly slow pace. At the end of 2015, a good 91 percent of all board positions in Dax companies were still occupied by men – whilst in MDax firms it was even 96 percent. The picture is far better, though still not good, in regulatory bodies: In Dax companies, 26 percent of all supervisory board members were female compared to 18 percent in MDax firms. “In many enterprises, cultural change in this respect would be highly desirable”, says Professor Dr. Hans-Joachim Böcking, co-author of the report and professor at Goethe University Frankfurt. Still: “At least as far as the basic salary of executive and supervisory board members is concerned, no gender-specific differences were detected either in Dax or MDax companies”, says Böcking.
A chairman on the supervisory board of a Dax company received an average total remuneration in 2015 of € 311,000. Deputies earned € 230,000, other supervisory board members € 127,500. Pay scales in MDax firms were far lower. Here companies considered their main overseer to be worth an average of € 183,500, the deputy was paid € 121,500 and the other members received € 75,000. Worth noting: Whilst the fixed remuneration for supervisory board members increased on average by about 12 percent in Dax and MDax companies, variable remuneration is still on the decline: in 2014, four out of ten Dax companies still made some form of variable payment. In 2015 it was only three out of ten.
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German Research Foundation funds film studies project by early career researchers for the first time
FRANKFURT. The first Research Training Group ever with a focus on film studies will be established in the course of the coming year at Goethe University Frankfurt. This was announced by the German Research Foundation on the 14th of November. In the framework of the RTG with the title “Configurations of Film”, twelve doctoral researchers and two post-docs will examine from 2017 onwards how film culture is changing in the context of advancing digitalisation in various areas.
Contemporary film culture is often referred to as the “post-cinematographic era”. Professor Vinzenz Hediger, scholar and film expert at the University who will also be the RTG’s speaker, remarks: “Film has expanded its reach more and more beyond public screenings in the cinema. With the proliferation of digital platforms, new forms are developing and new patterns of cinematic experience emerge.” At the same time, film serves increasingly as a creative template in theatre, fine arts and music. Hediger says: “As films circulate ever more widely, they affect other art forms and have a growing impact on other areas of life, including interpersonal communication. This increasing presence of filmic images and formats in all areas of life also constitutes a growing societal challenge.”
The “Configurations of Film” RTG of the German Research Foundation wants to take on this challenge by investigating the current transformations of film and their impact on other art forms and areas of life from an interdisciplinary perspective. The RTG combines an emphasis on historical research with systematic and comparative perspectives; in addition, the programme will use digital methods for film analysis and data mining on the internet, with which, for example, the proliferation of new film formats via platforms such as YouTube or Vimeo can be tracked.
The Research Training Group will build on successful cooperation between Goethe University Frankfurt and the German Film Institute (Deutsches Filminstitut), which together run the Masters degree programme in “Film Culture: Archiving, Programming, Presentation”, and profit from links to other cultural institutions in the Rhine-Main region. The RTG also builds on the interdisciplinary Masters degree programme in “Aesthetics”, which is unique to Frankfurt and in which all the disciplines participating in the RTG are also involved.
Twelve doctoral researchers and two post-docs, who can apply for a German Research Foundation scholarship in the framework of the Research Training Group, will start with their research in 2017. They will be supervised and mentored by 15 researchers from six universities: Goethe University Frankfurt, Offenbach University of Art and Design, Johannes Gutenberg University Mainz, the University of Mannheim and Philipps University Marburg. Alongside film studies and media studies, the disciplines involved include theatre studies, philosophy, musicology, literary studies and sociology. The RTG has an international focus and cooperates with the film studies programmes at Yale University (New Haven, USA) and Concordia University (Montreal, Canada). Funding amounts to about € 3.3 million for the first phase from 2017 to 2022.
In the spirit of the “citizen’s university”, the study programme will include a series of public lectures and events, for example at b3, the Biennale of the Moving Image, and at the cinema of the German Film Museum (Deutsches Filmmuseum), in the framework of which the RTG’s themes and research questions will be discussed in public and address a broader audience.
Further information: Professor Dr. Vinzenz Hediger, Department of Drama, Film and Media Studies, Westend Campus, Tel.: +49(0)69-798-32079, Email: email@example.com
ABCE1 splits the ribosome by means of a rotational motion after protein synthesis
FRANKFURT. Translation of the genetic code in proteins is a central process in life and takes place in the ribosome, a giant molecule consisting of two subunits. This is where long chains of amino acids are formed like on an assembly line. An interdisciplinary research group from Goethe University Frankfurt, the EMBL in Heidelberg, and the Gene Center of the University of Munich (LMU) has now succeeded in solving the structure of a central player in this process bound to the small ribosomal subunit: the protein containing a unique iron-sulphur domain with the nickname “Iron Hammer” splits the two subunits of the ribosome when a protein chain is completed so that production of a new protein can begin.
The two subunits of the ribosome have to be actively split once the protein chain is complete otherwise errors occur in mRNA translation: research ignored this fact for a long time. Central player in this “ribosome recycling” process is the essential and highly dynamic metalloenzyme ABCE1. The iron-sulphur domain of ABCE1, known as the “Iron Hammer”, rotates and presses the ribosomal subunits apart like a lever.
To uncover this, the research group led by Professor Robert Tampé at the Institute of Biochemistry at Goethe University Frankfurt isolated a complex of the small ribosomal subunit with ABCE1 (post-splitting complex) by means of an innovative preparation method. This complex was chemically fixed and cut into pieces, while the original distance information was preserved.
At the EMBL in Heidelberg, the researchers used highly advanced mass spectrometry to analyse these small fragments and relate them to each other revealing their original distances on nanometre scale. The group in Munich then examined the reconstructed complex with a high-resolution cryogenic electron microscope and was able to reconstruct a 3D model of the post-splitting complex with tightly bound ABCE1 from a vast collection of single-particle images.
Professor Robert Tampé summarizes the significance of these results: “We have forced the rebellious and aggressive multi-domain enzyme ABCE1 into a new, unexpected state on the ribosome and used the combined expertise of three institutes to enrich textbook knowledge for coming generations of students.”
Publication: Kristin Kiosze-Becker, Alessandro Ori, Milan Gerovac, André Heuer, Elina Nürenberg-Goloub, Umar Jan Rashid, Thomas Becker, Roland Beckmann, Martin Beck & Robert Tampé (2016): Structure of the Ribosome Post-Recycling Complex Probed by Chemical Cross-Linking and Mass Spectrometry. Nature Communications, doi: 10.1038/NCOMMS13248
Further information: Professor Dr. Robert Tampé, Institute of Biochemistry, Riedberg Campus, Tel.: +49(0)69-798-29475, firstname.lastname@example.org.
Goethe University Frankfurt develops OECD test with the freshwater mudsnail
FRANKFURT. Regulatory authorities around the world can in future instruct manufacturers of chemicals and drugs to check their products for harmful effects on reproduction by means of a new test with molluscs. After over 10 years of funding by the German Environment Agency in Dessau, a project coordinated by Goethe University Frankfurt has now resulted in an OECD guideline (Organisation for Economic Co-operation and Development) for global chemical testing. The test analyses in the laboratorythe long-term effects of chemicals on reproduction in freshwater mudsnails (Potamopyrgus antipodarum).
“Although this tiny creature is not an indigenous snail species, as what is known as a “model organism” its biological answers are also transferable to other molluscs, regardless of whether they stem from Europe, Asia or America”, explains Professor Jörg Oehlmann, coordinator of the test development team and head of the Department of Aquatic Ecotoxicology at Goethe University Frankfurt. Potamopyrgus is a water dweller and was introduced to Europe in the mid 19th century on board ships from New Zealand. However, this alien species is meanwhile part of the normal landscape in many of Europe’s watercourses.
New chemicals which have not yet been approved and harm the mudsnail in OECD Test No. 242 in the laboratory would have the same effect on it and related species in the wild. Since molluscs, after insects and crustaceans, are the second most species-rich group in the animal kingdom, the loss of these organisms would be fatal for biodiversity and thus also for the correct functioning of the ecosystems. The development of the “snail test” therefore constitutes an important contribution to keeping our watercourses clean and healthy, since substances which show a toxic effect in this test for the snail can in future be identified and controlled prior to market introduction.
In addition, the new snail test closes an existing gap in the environmental risk assessment of chemicals, since standardized tests with invertebrates to date focussed mainly on arthropods (insects and crustaceans). Snails had, however, in the past proven to be extraordinarily sensitive to a large number of harmful substances, including tributyltin compounds and other environmental chemicals which influence the hormone system.
The work coordinated by Goethe University Frankfurt on the development and standardization of the snail test took place over a period of more than 10 years. Test conditions for the snails with regard to water and feedstuff quality, temperature, concentration and numerous other parameters were optimized in the framework of an extensive research programme. In the last six years, four final validation studies with six test substances were carried out in 16 laboratories in Europe and the USA which showed that the test protocol developed is robust and the test generates reproducible results, independent of in which laboratory it is implemented.
For the test, female mudsnails are exposed to a concentration range of chemicals in ambient water. The organisms remain with the test substance in their test beakers for 28 days, after which the number of embryo amongst all surviving females is counted. “It’s a process which is easy to use and also suitable for everyday use by water authorities”, says Oehlmann.
In their home country of New Zealand, both male and female mudsnails are found. In Europe, however, populations are composed solely of females which reproduce parthenogenetically. This makes using the test and analysing the results easier, all the more so since the tiny snail makes only modest demands on the laboratory. “The animal’s small size has another advantage: in comparison to many other test procedures, this test can be miniaturized and doesn’t take up much space”, explains Oehlmann. That makes it possible to test a larger number of chemicals.
Further information: Prof. Dr. Jörg Oehlmann, Department of Aquatic Ecotoxicology, Riedberg Campus, Tel.: +49(0)69-798-42142, email@example.com
OECD guideline 242 for the testing of chemicals: http://dx.doi.org/10.1787/9789264264311-en.