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Study from CABD describes a key mechanism to improve the elimination of defective proteins and boost cellular health
published on 05/11/2024
The study, developed at the Andalusian Center for Developmental Biology, shows how cells adapt to stress conditions that induce the unfolding of proteins by activating the assembly of the machinery responsible for their destruction.
A research team led by the 'Nuclear Architecture and Dynamics' group of the Andalusian Center for Developmental Biology of Seville (CSIC - UPO - Junta de Andalucía) together with collaborators from Yale University (Connecticut, USA), has revealed a cellular mechanism that allows cells to optimize the elimination of misfolded proteins in stressful situations. This breakthrough, which facilitates the maintenance of cellular health and function, has been published in the journal iScience and represents a significant step forward in the field of cell biology and research into degenerative diseases.
From left to the right: Rafael R. Daga, Eduardo Díaz Pérez, Gabriel Ruiz Romero , Silvia Salas Pino , Mª Dolores Berdún Reina and Paula Ochoa Mejía.
The study, conducted in the yeast Schizosaccharomyces pombe as a model organism and led by the professors of the Genetics Area of the Pablo de Olavide University Silvia Salas Pino and Rafael R. Daga, in collaboration with the team of Professor Mark Hochstrasser at Yale, shows how cells are able to adapt to stress conditions, such as heat, by activating a rapid assembly system of proteasomes, complexes responsible for breaking down and eliminating defective proteins, which is essential to prevent the accumulation of “cellular junk” and avoid the associated toxicity that could compromise cell survival.
The importance of an efficient protein elimination system
Proteins must maintain a specific three-dimensional structure to perform their functions in cells. However, under stress conditions or with aging, these proteins can lose their structure and generate defective proteins that, if not properly eliminated, accumulate in cells in the form of toxic aggregates. This process, known as proteotoxicity, is linked to neurodegenerative diseases such as Alzheimer's and Parkinson's disease.
The authors of this study describe that heat stress-induced protein unfolding activates a cellular response that triggers an overall increase in proteasome activity, promoting the rapid assembly of new proteasomes from smaller building blocks that are pre-assembled and available in cells. This allows the system to respond efficiently and prevent the accumulation of misfolded proteins. The cells also replenish these subunits to ensure that the degradation system is always ready for future stress events, keeping the defense system primed.
“When we interfere with these proteasome assembly pathways through mutations, cells begin to accumulate protein aggregates, a process that severely affects their growth and makes them resemble aging cells.
These can be used as biosensors in the search for new drugs that prevent protein aggregation,” explain Silvia Salas and Rafael R. Daga, professors and researchers at the UPO.
Due to mutations, stress conditions or aging itself, proteins unfold. Cells try to refold these proteins by means of molecular chaperones (1), and if they fail to do so, the misfolded proteins are tagged with a ubiquitin molecule (2), presented to the proteasome (3) and degraded by it thanks to the proteolytic activity found in the center of its cylindrical structure (4). When this system is inefficient, misfolded proteins aggregate together and these aggregates can become toxic to cells.
A breakthrough towards new applications and therapies
This study not only represents a breakthrough in the understanding of proteostasis or protein balance in cells, but has also enabled the development of a platform for screening new drugs that is currently offered as a UPO-Tec service at the Universidad Pablo de Olavide, and which is developed at the Robotized Platform for Cellular Interactions of the Andalusian Center for Developmental Biology with the support of the María de Maeztu project of excellence granted to the CABD, with the aim of identifying and evaluating therapies that prevent the accumulation of defective proteins and promote cellular health.
The work has been developed at the Andalusian Center for Developmental Biology, a joint center of the Spanish National Research Council, Pablo de Olavide University and the Andalusian Regional Government, and its authors are Gabriel Ruiz Romero (graduate of the Biotechnology Degree of the UPO), Mª Dolores Berdún Reina (graduate of the Biotechnology Degree of the UPO), Mark Hochstrasser (Yale U. Professor, USA) and the professors of the Genetics Area of the UPO Silvia Salas Pino and Rafael Rodríguez Daga.
Ruiz-Romero, G., Berdún, M.D., Hochstrasser, M., Salas-Pino, S., Daga, R.R., Limiting 20S proteasome assembly leads to unbalanced nucleo-cytoplasmic distribution of 26S/30S proteasomes and chronic proteotoxicity in fission yeast, iSCIENCE (2024), DOI: 10.1016/j.isci.2024.111095
This press release was elaborated in collaboration with the UPO's Communication department
