Two young Brazilian researchers established in the United States have discovered that without a certain protein, eukaryotic beings, such as fungi, plants and animals (including humans), are unable to perform a vital survival function: destroying proteins wrongly produced by their own cells. Organisms without the protein listerin lack the ability to identify certain types of newly made aberrant proteins and to eliminate them by means of their cell quality control system. This conclusion is part of a study published on September 23 in the scientific journal Nature by Claudio Joazeiro, a 42-year old biochemist that heads a laboratory at the Scripps Research Institute in La Jolla (California), and Mario Bengtson, aged 35, who is working on his post-doctorate there. The lack of listerin leads to an accumulation of toxic proteins within the cells, the excess of which may be connected with the onset of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s.
“It was almost by accident that we discovered the role of listerin in this process,” says Joazeiro, who studies cell regulation mechanisms. A few years ago the Brazilian researcher and molecular biologist Steve Kay, now at the University of California in San Diego (UCSD), showed that mice with a mutation in the LISTER gene, which is responsible for producing listerin, developed motor neuron problems in their spinal cord. As this type of neurodegenerative disorder seems to be unleashed by too much defective protein, Joazeiro and Bengtson decided to investigate whether the gene, which virtually all eukaryotic organisms carry, from yeasts to humans, might not be important for the proper functioning of the cell cleaning process. They switched off, in the Saccharomyces cerevisiae yeast, a gene called LTN1 (equivalent to the LISTER gene) and found that its cells became incapable of recognizing and destroying some forms of aberrant proteins, so that they ended up dying. With no listerin, cell quality control failed. “Working with yeast is cheap and has the advantage of providing results fast,” comments Bengtson.
The Brazilians not only discovered what listerin does, but also how it plays its role as a cell sentinel, accusing the presence of defective proteins. Listerin bonds with ribosomes, the cell structures that synthesize proteins based on the genetic information of messenger RNA, and marks the newly made defective proteins with a type of chemical label of death: molecules of ubiquitin, a family of proteins that are fundamental for the cell regulation process. The ubiquitins were thus named for their ubiquity, as they are found in virtually all the cells of eukaryotic organisms. Aberrant (or unnecessary) proteins carrying this chemical marker for their destruction are directed to the proteasomes, structures that degrade these proteins and reduce them to chemical chains with a few aminoacids.
The listerin in ribosomes binds the ubiquitin molecules into a specific form of aberrant protein: those coded with RNA messengers that lack the so-called termination codon. “It tells the ribosome that the synthesized protein has reached the end of the road,” explains Joazeiro. In the absence of this codon, therefore, the ribosome continues adding aminoacids unduly until it comes to the end of the messenger RNA ribbon, generating an aberrant protein that cannot be corrected by the quality control systems. Another function of the termination codon is to signal to the ribosome that it is time to release the protein and to separate from the messenger RNA. “When this codon is missing, the RNA and the protein get stuck to the ribosome.” So that no accumulation of toxic material occurs within the cells and to release the “stuck” ribosomes, the listerin-ubiquitin system goes into action and puts the death label on the defective protein.
For the last 15 years at least, scientist from various laboratories have been trying to find in eukaryotes (beings endowed with cells containing a nucleus surrounded by a membrane with several organelles) the mechanism involved in the identification and elimination of aberrant proteins with no termination codon. These searches led nowhere because the researchers were following a deceptive clue, even though it appeared to be logical and correct. In bacteria, less elaborate prokaryotic beings, it was already a known fact that a molecule called tmRNA bonded with ribosomes that were “stuck” with the aberrant proteins and acted as a destruction marker for these defective proteins. For quite a long time, biochemists sought in the eukaryotes a molecule equivalent to tmRNA, which, they imagined, might also be responsible for performing the same function. However, the strategy did not pay off. Success was only attained when Joazeiro and Bengtson thought about the issue from another point of view and decided to study listerin.
ALS or Alzheimer
In addition to advancing the basic understanding of an important protein quality control mechanism, the Brazilians’ discovery might have implications in the translational research area, which bridges the gap between the findings of academia and the development of new treatments and medical drugs. In mice, switching off the LISTER gene leads to a disturbance known to cause neurodegenerative problems. “We now plan to try to establish the relation between the mouse illness and a human neurodegenerative disease,” says Bengtson. It is still too early to reach any conclusions, but one can speculate. The motor symptoms and the loss of spinal cord neurons remind us of amyotrophic lateral sclerosis (ALS) or similar diseases, while the accumulation of Tau protein in the animals’ brains might point to Alzheimer’s,” states Joazeiro.
Translational research is a field with which Brazilians are familiar, especially Joazeiro. After he graduated from and completed his master’s degree at the Chemistry Institute of the University of São Paulo (IQ-USP), this native of Bahia state did his doctorate at the University of California in San Diego (UCSD) in the early 1990’s. Ever since, has been established in this Californian city, which is a biotechnology center. First, he worked for the Salk Institute, then for the Novartis Research Foundation (GNF) and now he is at Scripps. The three centers combine basic and applied research. Bengtson has been on Joazeiro’s team for the last four years. “Both are excellent researchers,” says Mari Sogayar, the IQ-USP senior professor that was Joazeiro’s master’s degree and Bengtson’s PhD advisor. “Claudio has always managed to flabbergast me. He did his master’s degree in just one year.’
BENGTSON, M. H. et al. Role of a ribosome-associated E3 ubiquitin ligase in protein quality control. Nature. v. 467, p. 470-73. 23 Sep. 2010.