In all eukaryotic organisms, genetic material is stored in the nucleus of the cell in the form of DNA. To be used, this DNA is first transcribed into messenger RNA in the cell cytoplasm, then translated into protein using ribosomes, small machines capable of decoding messenger RNA to synthesize the appropriate proteins.
However, the speed at which this mechanism takes place is not uniform: it must adapt to allow the protein to adopt the correct configuration. Indeed, a deregulation of the production rate leads to structural defects. Proteins that are not folded correctly will aggregate, become unusable and often toxic to the cell. By analyzing the rate of movement of ribosomes in yeast cells, a team from the University of Geneva (UNIGE), Switzerland, in collaboration with the University of Hamburg, succeeded in demonstrating that the rate of protein synthesis is modulated by regulatory factors that alter the rate of translation of messenger RNA into proteins. These results are available in the journal Cell reports.
Proteins are 3D structures which, in order to act, must interlock with each other or interact with partners. In the event of a structural defect, the proteins clump together, becoming toxic and potentially pathological. This phenomenon is indeed observed in many neurodegenerative diseases, such as Alzheimer’s disease or amyotrophic lateral sclerosis.
We already knew that the speed of protein production varies according to needs: sometimes fast, sometimes very slow. However, we did not yet know how this mechanism was controlled. “
Martine Collart, Professor, Department of Microbiology and Molecular Medicine, UNIGE Faculty of Medicine
To understand this process, the scientists used a very innovative and still little-known technique: ribosome profiling. “This methodology makes it possible to determine the position of the ribosomes at a given moment in the cell”, explains Olesya Panasenko, researcher at Martine Collart’s laboratory and responsible for the “BioCode: RNA to Proteins” platform at the Faculty of Medicine, which is specializes in this technique. “It consists in degrading, at a precise moment, all the RNA which are not protected by the ribosome, to keep only the protected fragments of the ribosome (RPF). We will then sequence these RPFs in order to define how many ribosomes were on the mRNA, and at what positions, at that particular time. This indicates the speed and efficiency of the translation. “
Scientists observed the speed and dynamics of protein production in natural yeast cells as well as in genetically modified yeasts, in order to identify possible differences according to the genetic code. During synthesis, small condensates of RNA and proteins appear in the cell, with the function of slowing the rate of ribosome production. “The formation of these condensates depends on the presence or absence of regulatory factors, known as No, which act as decelerators,” explains Martine Collart. In their absence, the mechanism accelerates in the wrong places and results in aggregated proteins.
A speed regulated by the genetic code
Thus, Not factors associate with the ribosome at specific times during protein synthesis, to slow down the ribosome during translation by condensing RNA and nascent protein. “One can wonder if this regulatory mechanism is affected during neurodegenerative diseases or with age”, ask the authors. It is therefore possible that small disturbances, adding to each other, ultimately have a large cumulative effect over time.
Allen, GE, et al. (2021) Not4 and Not5 modulate translation prolongation by Rps7A ubiquitination, Rli1 blackening and condensates which exclude eIF5A. Cell reports. doi.org/10.1016/j.celrep.2021.109633.