News from the Institute
Tandem Mass Tag research award for Kevin Klann.
Kevin Klann, PhD student in the Münch group, receives the Tandem Mass Tag (TMT) bronze level research award 2020 by ThermoFisher Scientific. This annual award is rewarded for presented projects based on their innovation and impact on the work in the field of proteomics. The prize is endowed with 5,000$ worth of mass spectrometry (MS) reagents to enable promising proteomics projects by the lab. The Münch lab recently published a novel MS-based approach to study protein dynamics in the journal Molecular Cell. The award-winning project by Kevin is planning to use this powerful method to study the cellular protein degradation system in its entirety by combining protein dynamics MS and small molecule/CRISPR-Cas9 libraries targeting proteases and the ubiquitin-proteasome system. Thus, it will be possible to study the effect of each individual component of the protein degradation network on the cellular proteome and physiology. Combination of all puzzle pieces will give rise to a new picture of the protein degradation system with implications to cell and disease biology.... (read more)
Double-hit therapeutic strategy against COVID-19
Scientists from IBC2 and collaborating teams identified the papain-like protease (PLpro) of SARS-CoV-2 as an essential viral enzyme and potential weak spot, which may even turn out to be its Achilles’ heel. PLpro is required for the processing of viral polypeptides and the assembly of new viral particles within human cells. In addition, SARS-CoV-2 uses this enzyme to dampen the anti-viral immune response, helping the virus to modulate the host’s immune system to its own benefit. By this, the virus can easily multiply and spread further. The team has demonstrated that pharmaceutical targeting of PLpro by a non-covalent inhibitor (GRL-0617) blocks virus spread and increases anti-viral immunity in human epithelial cells, the prime site of pathogen entry. The respective results are now made publicly available on a preprint server.... (read more)
“Big Ideas” Essay from Ivan Đikić
World Health Day: “Big Ideas” on biomedical challenges.
The European Investment Bank (EIB) regularly invites international thought leaders to write about the most important issues of the day, an essay series dubbed “Big Ideas”. On the occasion of Croatia’s presidency of the EU Council, Croatian-born IBC2 Director Ivan Đikić was asked to contribute his view on the role of modern science in advancing healthcare. In his essay, he analyses the biomedical challenges ahead of us, especially with respect to common diseases like cancer and neurodegeneration, but also those emerging from novel viruses, rare diseases, and – last not least – from environmental and societal changes. He writes about the endurance needed for translational science to succeed, how progress has often lagged behind expectations and why technologies are the key to success. Finally, he shares his thoughts about a needed culture change with respect to drug discovery to ensure fair access of scientific progress around the globe and throughout societies.... (read more)
Münch group describes coronavirus infection & potential therapies.
SARS-CoV-2 infection profile and therapeutic strategies.
Since the beginning of 2020, a new coronavirus (SARS-CoV-2) has been spreading, leading to a pandemic with > 126,000 infections around the globe recorded until today. In people, the virus causes a disease named COVID-19, which can cause severe respiratory failure and has already led to more than 4,600 deaths. The mechanisms by which SARS-CoV-2 enters cells, how the cell responds to infection, and which therapeutic approaches could stop viral replication remain unclear. Now, IBC2 group leader Christian Münch, together with Jindrich Cinatl (Institute of Medical Virology, University Hospital Frankfurt), provides some answers to these questions. Using SARS-CoV-2 isolated from COVID-19 patients in Frankfurt, they established a cellular model to study coronavirus infection. Using a recently developed novel translation proteomics method, they analysed how viral infection changes cellular protein synthesis and abundance. This revealed several cellular pathways strongly modulated upon SARS-CoV-2 infection. Strikingly, using drugs targeting these pathways – some of which are approved for use in other diseases – prevented SARS-CoV-2 replication in cells. This reveals potential new therapeutic strategies for specific COVID-19 treatments.... (read more)
Bremm group reports: Deubiquitinases (DUBs) are regulated by hydroxylation.
DUBs are vital for the regulation of ubiquitin signals, and both their catalytic activity and their target selection needs to be tightly controlled. As reported in today’s issue of the Journal of Biological Chemistry, the group of Anja Bremm identified asparagine hydroxylation as a novel post-translational modification involved in the regulation of the DUB Cezanne. Cezanne controls essential cellular functions and signaling pathways. The team demonstrated for the first time that the predicted ubiquitin-binding domain (UBD) in Cezanne is functionally active and interacts with ubiquitin in a unique manner. At the same time, they discovered a novel regulatory mechanism: Hydroxylation within this domain inhibits ubiquitin binding and therefore may affect Cezanne’s ability to bind specific target proteins via its UBD. Hydroxylation is carried out by FIH1 (factor inhibiting HIF1), which is a key regulator of the cellular oxygen sensing machinery, and the reaction is dependent on oxygen levels.... (read more)