Accumulation of misfolded or damaged proteins can have catastrophic effects on cell function and viability. As protection, cells have protein quality control (PQC) pathways that detect aberrant proteins and either try to repair them by refolding them into their native structure or eliminate them through degradation. In eukaryotes, PQC degradation pathways have been characterized in the cytoplasm, secretory pathway and mitochondria. However, no such pathways were known in the nucleus, where non-native structures can also arise as protein subunits are displaced from complexes during normal nuclear processes such as chromatin remodeling, RNA transcription and DMA replication. We have recently discovered the first eukaryotic nuclear quality control pathway using the model system, S. cerevisiae. It is defined by the ubiquitin-protein ligase San1. Loss of SAN1 causes a chronic stress response and cellular toxicity when aberrant proteins are present in the nucleus, a phenotype similar to the toxicity of nuclear protein aggregates associated with diseases such as Huntington's disease and Oculopharyngeal Muscular Dystrophy. We suggest that San1- mediated degradation acts as a defense against the deleterious accumulation of proteins in the nucleus, and that analogous systems are conserved throughout eukaryotes. We are now in a unique position to take advantage of biochemical and genetic approaches available in S. cerevisiae to determine how this pathway detects and destroys aberrant nuclear proteins, and to identify the additional pathways by which aberrant proteins are prevented from accumulating in the nucleus. This work will likely provide insight into how these processes may be altered in human diseases in which nuclear protein aggregation plays a role.
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