FRANKFURT. When cells are stressed, they initiate a complex and
precisely regulated response to prevent permanent damage. One of the immediate
reactions to stress signals is a reduction of protein synthesis (translation). Until
now, it was difficult to measure such acute cellular changes. As reported in
the latest online issue of the renowned journal Molecular Cell, researchers at Goethe University have now developed
a method overcoming this hurdle.
The team led by biochemist Dr. Christian
Münch, who heads an Emmy Noether Group, employs a simple but extremely
effective trick: when measuring all proteins in the mass spectrometer, a booster
channel is added to specifically enhance the signal of newly synthesised
proteins to enable their measurement. Thus, acute changes in protein synthesis
can now be tracked by state-of-the-art quantitative mass spectrometry.
The idea emerged because the team wanted
to understand how specific stress signals influence protein synthesis. "Since
the amount of newly produced proteins within a brief time interval is rather
small, the challenge was to record minute changes of very small percentages for
each individual protein," comments group leader Münch. The newly developed
analysis method now provides his team with detailed insight into the molecular
events that ensure survival of stressed cells. The cellular response to stress
plays an important role in the pathogenesis of many human diseases, including cancer
and neurodegenerative disorders. An understanding of the underlying molecular
processes opens the door for the development of new therapeutic strategies.
"The method we developed enables highly
precise time-resolved measurements. We can now analyse acute cellular stress
responses, i.e, those taking place within minutes. In addition, our method
requires little material and is extremely cost-efficient," Münch explains.
"This helps us to quantify thousands of proteins simultaneously in defined
time spans after a specific stress treatment." Due to the small amount of material
required, measurements can also be carried out in patient tissue samples, facilitating
collaborations with clinicians. At a conference on Proteostatis (EMBO) in
Portugal, PhD student Kevin Klann was recently awarded with a FEBS journal poster
prize for his presentation of the first data produced using the new method. The
young molecular biologist demonstrated for the first time that two of the most
important cellular signaling pathways, which are triggered by completely
different stress stimuli, ultimately results in the same effects on protein
synthesis. This discovery is a breakthrough in the field.
The project is funded by the European Research
Council (ERC) as part of Starting Grant "MitoUPR", which was awarded
to Münch for studying quality control mechanisms for mitochondrial proteins. In
addition, Christian Münch has received funding within the German Research
Foundation's (DFG, Deutsche
Forschungsmeinschaft) Emmy Noether Programme and is a member of the Johanna
Quandt Young Academy at Goethe. Since December 2016, he has built up a group on
"Protein Quality Control" at the Institute for Biochemistry II at Goethe
University's Medical Faculty, following his stay in one of the leading
proteomic laboratories at Harvard University.
Further information:
Dr. Christian Münch, Institute for Biochemistry II, Faculty of Medicine, Goethe University, Tel.: +49 69
6301-6599, ch.muench@em.uni-frankfurt.de.
Publication:
Klann
K, Tascher G, Münch C. Functional translatome proteomics reveal converging and
dose-dependent regulation by mTORC1 and eIF2α. Molecular Cell 77, 1-13, Feb 20, 2020.
doi.org/10.1016/j.molcel.2019.11.010