Cell Biology Select

The accumulation of misfolded proteins occurs during cellular stress and aging and is a common feature of many neuro-degenerative disorders. Recent work provides insights into the mechanisms by which cells detect and respond to the presence of misfolded proteins. This includes the discovery that misfolded proteins preferentially accumulate in one of two cellular compartments. Other new findings reveal proteins involved in the retrotranslocation of misfolded glycopro-teins, uncover mechanisms regulating proteolysis of misfolded proteins, and suggest new strategies for the treatment of diseases associated with protein aggregation. According to new work by Kaganovich et al. (2008), different classes of misfolded proteins partition to two separate intracellular compartments, one next to the nucleus (juxtanuclear) and the other near vacuoles (perivacuolar). By examining the cellular distribution of multiple misfolded proteins in both yeast and mammalian cells, the authors propose a stunningly simple model: soluble ubiquitinated proteins go to the juxtanuclear compartment, whereas insoluble terminally misfolded proteins accumulate in the perivacuolar compartment. In addition to the spatial segregation, the fate of the proteins in these two compartments appears to be equally divergent. For example , proteins in the juxtanuclear compartment are in close proximity to cytoplasmic concentrations of the 26S proteasome, whereas the perivacuolar compartment is marked by proteins implicated in autophagy. Although in most cases the juxtanuclear compartment appears to be the compartment of first resort for protein quality control, the authors demonstrate that disease-causing Huntingtin and prion proteins preferentially partition to the perivacuolar compartment. Is this preferential sorting a mechanism of cellular protection that sequesters these dangerous proteins for long-term storage and disposal? Or does this reflect the fact that these misfolded proteins interact inefficiently with the normal quality-control machinery and as a consequence are shunted to the perivacuolar pathways by default? Although this question is unresolved, the answer may be highly relevant to understanding the pathogenesis of diseases associated with protein misfolding. Intriguingly, the authors demonstrate that enhancing the ubiquitination of a prion protein enhances its partitioning to the juxtanuclear compartment. Likewise, blocking the ubiquitination of proteins that normally go to the juxtanuclear compartment leads them to partition to the perivacuolar protein. If enhancing the partitioning of misfolded proteins that cause disease to one of these compartments were to lessen their toxicity, these efforts might form the basis of a cellular assay with which researchers can screen for new therapeutic compounds. How do you clear toxic aggregates of unhealthy proteins that …