Role of the protein quality control system in basal and stress conditions in fission yeast

Resumen

The concentrations, native structures and inter-molecular interactions of the different proteins of a given proteome have to be tightly controlled, and this is referred to as proteostasis. This balance is constantly challenged by intrinsic and extrinsic factors that must be buffered by the protein quality control (PQC) system, which is composed of a large network of molecular chaperones and the degradation components of the ubiquitin proteasome system (UPS) and autophagy. In fact, many pathological or physiological processes such as neurodegenerative diseases, cancer and aging are associated with the failure of the PQC system. During this thesis project, we have characterized the PQC pathways of Schizosaccharomyces pombe, a model system for which very little was known about proteostasis control in basal or stress conditions. First, we have studied how the UPS helps maintaining the proper protein concentrations of transcription factors at basal conditions. This turns out to be a very important process for the regulation of signal transduction cascades. In particular, we have characterized the mechanisms and identified the UPS components involved in the degradation of the transcription factor Pap1, which levels are tightly controlled in a sub-cellular localization dependent manner. Second, the accumulation of protein aggregate centers in cells has been traditionally linked to toxicity, even though positive roles have recently been assigned to these foci. We were interested in studying the participation of aggregation-prone proteins in toxic and/or beneficial effects. To this end, we have characterized the expression of ‘humanized’ fission yeast cells, by expressing in this model system the neurodegenerative diseases-related proteins reporters HttNTD.nQ and TDP-43 in fission yeast. Our experiments sug-gest that moderate concentrations of some specific types of aggregates can contribute to cell fitness and promote lifespan extension.