Spatial protein quality control and the evolution of lineage-specific ageing

Nyström, Thomas

doi:10.1098/rstb.2010.0282

Cited by 28 publications

(27 citation statements)

References 43 publications

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“…One strategy for clearing aggregation is during mitosis, where cytoplasmic protein aggregates can be segregated asymmetrically into one cell, thus keeping the other cell pristine [26, 30]. This uneven inheritance is proposed to contribute to the aging of the cell acquiring the damage [26, 119], and has been best studied in budding yeast, which naturally divide asymmetrically to produce mother and daughter cells.…”

Section: Spatial Management Of Toxic Protein Aggregation In the Nucleusmentioning

confidence: 99%

How the Nucleus Copes with Proteotoxic Stress

Shibata

Morimoto

2014

Current Biology

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Summary The proper folding of proteins is continuously challenged by intrinsic and extrinsic stresses, and the accumulation of toxic misfolded proteins is associated with many human diseases. Eukaryotic cells have evolved a complex network of protein quality control pathways to protect the proteome, and these pathways are specialized for each subcellular compartment. While many details have been elucidated for how the cytosol and endoplasmic reticulum counteract proteotoxic stress, relatively little is known about the pathways protecting the nucleus from protein misfolding. Here, we offer a conceptual framework for how proteostasis is maintained in this organelle. We define the particular requirements that must be considered for the nucleus to manage proteotoxic stress, summarize the known and implicated pathways of nuclear protein quality control, and identify the unresolved questions in the field. Proper maintenance of nuclear proteostasis has important implications in preserving genomic integrity, as well as for aging and disease.

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Section: Spatial Management Of Toxic Protein Aggregation In the Nucleusmentioning

confidence: 99%

How the Nucleus Copes with Proteotoxic Stress

Shibata

Morimoto

2014

Current Biology

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“…These quality control mechanisms are highly conserved and essentially consist of chaperones and proteases that, respectively (re)fold or hydrolyze unfolded, misfolded, and aggregated proteins (17)(18)(19)(20)(21)(22). In spite of this elaborate protein homeostasis network, however, the accumulation and aggregation of misfolded proteins to some extent remain inevitable (5,23), and recent studies have forwarded spatial organization as another important strategy of dealing with PAs inside the cell (24).…”

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confidence: 99%

“…These reporter systems have in turn revealed the specific sequestration and asymmetric inheritance of cellular PAs during growth and division in bacteria (2,11,25), yeast (4), and higher eukaryotes (26), altogether suggesting a general rejuvenation strategy through which cytotoxic PAs preferentially remain linked to the older compartment upon cell division (24). In the Escherichia coli model system, for example, the polar localization and subsequent asymmetric segregation of cellular PAs were shown to be at least partially responsible for the previously observed pattern of aging in clonal lineages of this bacterium.…”

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confidence: 99%

In Vivo Disassembly and Reassembly of Protein Aggregates in Escherichia coli

2014

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Protein misfolding and aggregation are inevitable but detrimental cellular processes. Cells therefore possess protein quality control mechanisms based on chaperones and proteases that (re)fold or hydrolyze unfolded, misfolded, and aggregated proteins. Besides these conserved quality control mechanisms, the spatial organization of protein aggregates (PAs) inside the cell has been proposed as an important additional strategy to deal with their cytotoxicity. In the bacterium Escherichia coli, however, it remained unclear how this spatial organization is established and how this process of assembling PAs in the cell poles affects cellular physiology. In this report, high hydrostatic pressure was used to transiently reverse protein aggregation in living E. coli cells, allowing the subsequent (re)assembly of PAs to be studied in detail. This approach revealed PA assembly to be dependent on intracellular energy and metabolic activity, with the resulting PA structure being confined to the cell pole by nucleoid occlusion. Moreover, a correlation could be observed between the time needed for PA reassembly and the individual lag time of the cells, which might prevent symmetric segregation of cytotoxic PAs among siblings to occur and ensure rapid spatial clearance of molecular damage throughout the emerging population. P rotein misfolding is an inevitable process in cellular life, often aggravated by genetic defects and/or a number of stresses encountered in the environment (1-6). Since misfolded proteins typically expose hydrophobic residues that are normally buried within their native structure, they tend to aggregate with each other into larger insoluble structures termed protein aggregates (PAs) (5). Misfolded and aggregated proteins not only reduce the concentration of functional proteins and squander the cellular time and energy invested in their translation (7) but also have been shown to be cytotoxic themselves by mediating aberrant interactions with other proteins (8), sequestering aids to cellular folding away from other (essential) proteins (9), and possibly even affecting the integrity of lipid membranes (10). As such, this interference can (progressively) compromise cellular fitness (3, 11) and even extrapolate into debilitating neurodegenerative diseases in humans (12)(13)(14).Due to the link with general cellular degeneracy, protein misfolding and aggregation are intensively studied processes in both prokaryotes and eukaryotes (15). Using a combination of biochemical, biophysical, structural, and genetic approaches, this has led to an extensive knowledge of protein quality control mechanisms and aggregation in vitro, as well as the identification of a number of genes involved in these processes (16-19). These quality control mechanisms are highly conserved and essentially consist of chaperones and proteases that, respectively (re)fold or hydrolyze unfolded, misfolded, and aggregated proteins (17)(18)(19)(20)(21)(22). In spite of this elaborate protein homeostasis network, however, the accumulation and aggrega...

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“…The processes of spatial quality control that cause damaged cellular components to be retained in the parent, thus rejuvenating the offspring but causing the parent to age, were discussed by Thomas Nyström [17]. Great strides have been made, particularly in budding yeast in identifying damaged molecules that undergo asymmetrical segregation and the genes and mechanisms involved.…”

Section: Introductionmentioning

confidence: 99%