Learn more: Protein Misfolding and Proteostasis

Cytoplasmic protein quality control degradation mediated by parallel actions of the E3 ubiquitin ligases Ubr1 and San1
Proc. Natl. Acad. Sci. U.S.A 2010, view full abstract in PubMed

Eukaryotic cells maintain proteostasis by quality control (QC) degradation. These pathways can specifically target a wide variety of distinct misfolded proteins, and so are important for management of cellular stress. Although a number of conserved QC pathways have been described in yeast, the E3 ligases responsible for cytoplasmic QC are unknown. We now show that Ubr1 and San1 mediate chaperone-dependent ubiquitination of numerous misfolded cytoplasmic proteins. This action of Ubr1 is distinct from its role in the "N-end rule." In this capacity, Ubr1 functions to protect cells from proteotoxic stresses. Our phenotypic and biochemical studies of Ubr1 and San1 indicate that two strategies are employed for cytoplasmic QC: chaperone-assisted ubiquitination by Ubr1 and chaperone-dependent delivery to nuclear San1. The broad conservation of Ubr ligases and the relevant chaperones indicates that these mechanisms will be important in understanding both basic and biomedical aspects of cellular proteostasis.

Meta-analysis of heat- and chemically upregulated chaperone genes in plant and human cells
Cell Stress. Chaperones. 2010, view full abstract in PubMed

Molecular chaperones are central to cellular protein homeostasis. In mammals, protein misfolding diseases and aging cause inflammation and progressive tissue loss, in correlation with the accumulation of toxic protein aggregates and the defective expression of chaperone genes. Bacteria and non-diseased, non-aged eukaryotic cells effectively respond to heat shock by inducing the accumulation of heat-shock proteins (HSPs), many of which molecular chaperones involved in protein homeostasis, in reducing stress damages and promoting cellular recovery and thermotolerance. We performed a meta-analysis of published microarray data and compared expression profiles of HSP genes from mammalian and plant cells in response to heat or isothermal treatments with drugs. The differences and overlaps between HSP and chaperone genes were analyzed, and expression patterns were clustered and organized in a network. HSPs and chaperones only partly overlapped. Heat-shock induced a subset of chaperones primarily targeted to the cytoplasm and organelles but not to the endoplasmic reticulum, which organized into a network with a central core of Hsp90s, Hsp70s, and sHSPs. Heat was best mimicked by isothermal treatments with Hsp90 inhibitors, whereas less toxic drugs, some of which non-steroidal anti-inflammatory drugs, weakly expressed different subsets of Hsp chaperones. This type of analysis may uncover new HSP-inducing drugs to improve protein homeostasis in misfolding and aging diseases.

RNA-mediated neurodegeneration in repeat expansion disorders
Ann. Neurol. 2010, view full abstract in PubMed

Most neurodegenerative disorders are thought to result primarily from the accumulation of misfolded proteins, which interfere with protein homeostasis in neurons. For a subset of diseases, however, noncoding regions of RNAs assume a primary toxic gain-of-function, leading to degeneration in many tissues, including the nervous system. Here we review a series of proposed mechanisms by which noncoding repeat expansions give rise to nervous system degeneration and dysfunction. These mechanisms include transcriptional alterations and the generation of antisense transcripts, sequestration of mRNA-associated protein complexes that lead to aberrant mRNA splicing and processing, and alterations in cellular processes, including activation of abnormal signaling cascades and failure of protein quality control pathways. We place these potential mechanisms in the context of known RNA-mediated disorders, including the myotonic dystrophies and fragile X tremor ataxia syndrome, and discuss recent results suggesting that mRNA toxicity may also play a role in some presumably protein-mediated neurodegenerative disorders. Lastly, we comment on recent progress in therapeutic development for these RNA-dominant diseases.