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1.
The accumulation of damaged and aggregated proteins is a hallmark of aging and increased proteotoxic stress. To limit the toxicity of damaged and aggregated proteins and to ensure that the damage is not inherited by succeeding cell generations, a system of spatial quality control operates to sequester damaged/aggregated proteins into inclusions at specific protective sites. Such spatial sequestration and asymmetric segregation of damaged proteins have emerged as key processes required for cellular rejuvenation. In this review, we summarize findings on the nature of the different quality control sites identified in yeast, on genetic determinants required for spatial quality control, and on how aggregates are recognized depending on the stress generating them. We also briefly compare the yeast system to spatial quality control in other organisms. The data accumulated demonstrate that spatial quality control involves factors beyond the canonical quality control factors, such as chaperones and proteases, and opens up new venues in approaching how proteotoxicity might be mitigated, or delayed, upon aging.  相似文献   

2.
Cellular toxicity introduced by protein misfolding threatens cell fitness and viability. Failure to eliminate these polypeptides is associated with various aggregation diseases. In eukaryotes, the ubiquitin proteasome system (UPS) plays a vital role in protein quality control (PQC), by selectively targeting misfolded proteins for degradation. While the assembly of the proteasome can be naturally impaired by many factors, the regulatory pathways that mediate the sorting and elimination of misassembled proteasomal subunits are poorly understood. Here, we reveal how the dysfunctional proteasome is controlled by the PQC machinery. We found that among the multilayered quality control mechanisms, UPS mediated degradation of its own misassembled subunits is the favored pathway. We also demonstrated that the Hsp42 chaperone mediates an alternative pathway, the accumulation of these subunits in cytoprotective compartments. Thus, we show that proteasome homeostasis is controlled through probing the level of proteasome assembly, and the interplay between UPS mediated degradation or their sorting into distinct cellular compartments.  相似文献   

3.
Genomes,proteomes, and dynamic networks in the cell nucleus   总被引:9,自引:6,他引:3  
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4.
In order to maintain cellular homeostasis and a healthy state, aberrant and aggregated proteins are to be recognized and rapidly cleared from cells. Parkinson's disease, known to be associated with multiple factors; presents with impaired clearance of aggregated alpha synuclein as a key factor. We endeavored to study microRNA molecules with potential role on regulating multiple checkpoints of protein quality control within cells. Carrying out global miRNA profiling in a transgenic C. elegans model that expresses human alpha synuclein, we identified novel miRNA, miR-4813-3p, as a significantly downregulated molecule. Further studying its putative downstream target genes, we were able to mechanistically characterize six genes gbf-1, vha-5, cup-5, cpd-2, acs-1 and C27A12.7, which relate to endpoints associated with alpha synuclein expression, oxidative stress, locomotory behavior, autophagy and apoptotic pathways. Our study reveals the novel role of miR-4813-3p and provides potential functional characterization of its putative target genes, in regulating the various pathways associated with PQC network. miR-4813-3p modulates ERUPR, MTUPR, autophagosome-lysosomal-pathway and the ubiquitin-proteasomal-system, making this molecule an interesting target for further studies towards therapeutically addressing multifactorial aspect of Parkinson's disease.  相似文献   

5.
The highly conserved ubiquitin-proteasome system (UPS) controls the stability of most nuclear and cytoplasmic proteins and is therefore essential for virtually all aspects of cellular function. We have previously shown that the UPS is impaired in the presence of aggregated proteins that become deposited into cytoplasmic inclusion bodies (IBs). Here, we report that production of protein aggregates specifically targeted to either the nucleus or cytosol leads to global impairment of UPS function in both cellular compartments and is independent of sequestration of aggregates into IBs. The observation of severe UPS impairment in compartments lacking detectable aggregates or aggregation-prone protein, together with the lack of interference of protein aggregates on 26S proteasome function in vitro, suggests that UPS impairment is unlikely to be a consequence of direct choking of proteasomes by protein aggregates. These data suggest a common proteotoxic mechanism for nuclear and cytoplasmic protein aggregates in the pathogenesis of neurodegenerative disease.  相似文献   

6.
7.
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.  相似文献   

8.
Knowledge of membrane receptor organization is essential for understanding the initial steps in cell signaling and trafficking mechanisms, but quantitative analysis of receptor interactions at the single-cell level and in different cellular compartments has remained highly challenging. To achieve this, we apply a quantitative image analysis technique—spatial intensity distribution analysis (SpIDA)—that can measure fluorescent particle concentrations and oligomerization states within different subcellular compartments in live cells. An important technical challenge faced by fluorescence microscopy-based measurement of oligomerization is the fidelity of receptor labeling. In practice, imperfect labeling biases the distribution of oligomeric states measured within an aggregated system. We extend SpIDA to enable analysis of high-order oligomers from fluorescence microscopy images, by including a probability weighted correction algorithm for nonemitting labels. We demonstrated that this fraction of nonemitting probes could be estimated in single cells using SpIDA measurements on model systems with known oligomerization state. Previously, this artifact was measured using single-step photobleaching. This approach was validated using computer-simulated data and the imperfect labeling was quantified in cells with ion channels of known oligomer subunit count. It was then applied to quantify the oligomerization states in different cell compartments of the proteolipid protein (PLP) expressed in COS-7 cells. Expression of a mutant PLP linked to impaired trafficking resulted in the detection of PLP tetramers that persist in the endoplasmic reticulum, while no difference was measured at the membrane between the distributions of wild-type and mutated PLPs. Our results demonstrate that SpIDA allows measurement of protein oligomerization in different compartments of intact cells, even when fractional mislabeling occurs as well as photobleaching during the imaging process, and reveals insights into the mechanism underlying impaired trafficking of PLP.  相似文献   

9.
Eukaryotic cells must contend with a continuous stream of misfolded proteins that compromise the cellular protein homeostasis balance and jeopardize cell viability. An elaborate network of molecular chaperones and protein degradation factors continually monitor and maintain the integrity of the proteome. Cellular protein quality control relies on three distinct yet interconnected strategies whereby misfolded proteins can either be refolded, degraded, or delivered to distinct quality control compartments that sequester potentially harmful misfolded species. Molecular chaperones play a critical role in determining the fate of misfolded proteins in the cell. Here, we discuss the spatial and temporal organization of cellular quality control strategies and their implications for human diseases linked to protein misfolding and aggregation.  相似文献   

10.
Transport carriers regulate membrane flow between compartments of the secretory and endocytic pathways in eukaryotic cells. Carrier biogenesis is assisted by microtubules, actin filaments and their associated motors that link to membrane-associated coats, adaptors and accessory proteins. We summarize here how the biochemical properties of membranes inform their interactions with cytoskeletal regulators. We also discuss how the forces generated by the cytoskeleton and motor proteins alter the biophysical properties and the shape of membranes. The interplay between the cytoskeleton and membrane proteins ensures tight spatial and temporal control of carrier biogenesis, which is essential for cellular homeostasis.  相似文献   

11.
Alterations occur within distal neuronal compartments, including axons and synapses, during the course of neurodegenerative diseases such as Parkinson’s disease (PD). These changes could hold important implications for the functioning of neural networks, especially since research studies have shown a loss of dendritic spines locating to medium spiny projection neurons and impaired axonal transport in PD-affected brains. However, despite ever-increasing awareness of the vulnerability of synapses and axons, inadequate understanding of the independent mechanisms regulating non-somatic neurodegeneration prevails. This has resulted in limited therapeutic strategies capable of targeting these distinct cellular compartments. Deregulated protein synthesis, folding and degrading proteins, and protein quality-control systems have repeatedly been linked with morphological and functional alterations of synapses in the PD-affected brains. Here, we review current understanding concerning the proteins involved in structural and functional changes that affect synaptic contact-points in PD. The collection of studies discussed emphasizes the need for developing therapeutics aimed at deregulated protein synthesis and degradation pathways operating at axonal and dendritic synapses for preserving “normal” circuitry and function, for as long as possible.  相似文献   

12.
The Ras GTPases act as binary switches for signal transduction pathways that are important for growth regulation and tumorigenesis. Despite the biochemical simplicity of this switch, Ras proteins control multiple pathways, and the functions of the four mammalian Ras proteins are not overlapping. This raises an important question—how does a Ras protein selectively regulate a particular activity? One recently emerging model suggests that a single Ras protein can control different functions by acting in distinct cellular compartments. A critical test of this model is to identify pathways that are selectively controlled by Ras when it is localized to a particular compartment. A recent study has examined Ras signaling in the fission yeast Schizosaccharomyces pombe, which expresses only one Ras protein that controls two separate evolutionarily conserved pathways. This study demonstrates that whereas Ras localized to the plasma membrane selectively regulates a MAP kinase pathway to mediate mating pheromone signaling, Ras localized to the endomembrane activates a Cdc42 pathway to mediate cell polarity and protein trafficking. This study has provided unambiguous evidence for compartmentalized signaling of Ras.  相似文献   

13.
Protein sorting by tyrosine-based signals: adapting to the Ys and wherefores   总被引:24,自引:0,他引:24  
The endocytic and secretory pathways of eukaryotic cells consist of an array of membrane-bound compartments, each of which contains a characteristic cohort of transmembrane proteins. Understanding how these proteins are targeted to and maintained within their appropriate compartments will be crucial for unravelling the mysteries of organelle biogenesis and function. A common event in the sorting of many transmembrane proteins is the interaction between a sorting signal in the cytosolic domain of the targeted protein and a component of an organellar protein coat. Here, we summarize recent findings on the mechanism of sorting by one type of signal, characterized by the presence of a critical tyrosine (Y) residue, and attempt to integrate these findings into a hypothetical model for protein sorting in the endocytic and late (post-Golgi) secretory pathways.  相似文献   

14.
Autophagy is a fundamental cellular process promoting survival under various environmental stress conditions. Selective types of autophagy have gained much interest recently as they are involved in specific quality control mechanisms removing, for example, aggregated proteins or dysfunctional mitochondria. This is considered to counteract the development of a number of neurodegenerative disorders and aging. Here we review the role of mitophagy and mitochondrial dynamics in ensuring quality control of mitochondria. In particular, we provide possible explanations why mitophagy in yeast, in contrast with the situation in mammals, was found to be independent of mitochondrial fission. We further discuss recent findings linking these processes to nutrient sensing pathways and the general stress response in yeast. In particular, we propose a model for how the stress response protein Whi2 and the Ras/PKA (protein kinase A) signalling pathway are possibly linked and thereby regulate mitophagy.  相似文献   

15.
Insulin signaling pathways in time and space   总被引:31,自引:0,他引:31  
Despite remarkable progress in dissecting the signaling pathways that are crucial for the metabolic effects of insulin, the molecular basis for the specificity of its cellular actions is not fully understood. One clue might lie in the spatial and temporal aspects of signaling. Recent evidence suggests that signaling molecules and pathways are localized to discrete compartments in cells by specific protein interactions. Also, the rapid termination of tyrosine or lipid phosphorylation by phosphatases or serine kinases might tightly control the strength of a signaling pathway, thus determining its effect on growth, differentiation and metabolism.  相似文献   

16.
Trafficking of proteins and RNAs is essential for cellular function and homeostasis. While it has long been appreciated that proteins and RNAs move within cells, only recently has it become possible to visualize trafficking events in vivo. Analysis of protein and RNA motion within the cell nucleus have been particularly intriguing as they have revealed an unanticipated degree of dynamics within the organelle. These methods have revealed that the intranuclear trafficking occurs largely by energy-independent mechanisms and is driven by diffusion. RNA molecules and non-DNA binding proteins undergo constrained diffusion, largely limited by the spatial constraint imposed by chromatin, and chromatin binding proteins move by a stop-and-go mechanism where their free diffusion is interrupted by random association with the chromatin fiber. The ability and mode of motion of proteins and RNAs has implications for how they find nuclear targets on chromatin and in nuclear subcompartments and how macromolecular complexes are assembled in vivo. Most importantly, the dynamic nature of proteins and RNAs is emerging as a means to control physiological cellular responses and pathways.  相似文献   

17.
To prevent the accumulation of misfolded and aggregated proteins, the cell has developed a complex network of cellular quality control (QC) systems to recognize misfolded proteins and facilitate their refolding or degradation. The cell faces numerous obstacles when performing quality control on transmembrane proteins. Transmembrane proteins have domains on both sides of a membrane and QC systems in distinct compartments must coordinate to monitor the folding status of the protein. Additionally, transmembrane domains can have very complex organization and QC systems must be able to monitor the assembly of transmembrane domains in the membrane. In this review, we will discuss the QC systems involved in repair and degradation of misfolded transmembrane proteins. Also, we will elaborate on the factors that recognize folding defects of transmembrane domains and what happens when misfolded transmembrane proteins escape QC and aggregate. This article is part of a Special Issue entitled: Protein Folding in Membranes.  相似文献   

18.
Proctor CJ  Lorimer IA 《PloS one》2011,6(7):e22038
Neurodegeneration is an age-related disorder which is characterised by the accumulation of aggregated protein and neuronal cell death. There are many different neurodegenerative diseases which are classified according to the specific proteins involved and the regions of the brain which are affected. Despite individual differences, there are common mechanisms at the sub-cellular level leading to loss of protein homeostasis. The two central systems in protein homeostasis are the chaperone system, which promotes correct protein folding, and the cellular proteolytic system, which degrades misfolded or damaged proteins. Since these systems and their interactions are very complex, we use mathematical modelling to aid understanding of the processes involved. The model developed in this study focuses on the role of Hsp70 (IPR00103) and Hsp90 (IPR001404) chaperones in preventing both protein aggregation and cell death. Simulations were performed under three different conditions: no stress; transient stress due to an increase in reactive oxygen species; and high stress due to sustained increases in reactive oxygen species. The model predicts that protein homeostasis can be maintained during short periods of stress. However, under long periods of stress, the chaperone system becomes overwhelmed and the probability of cell death pathways being activated increases. Simulations were also run in which cell death mediated by the JNK (P45983) and p38 (Q16539) pathways was inhibited. The model predicts that inhibiting either or both of these pathways may delay cell death but does not stop the aggregation process and that eventually cells die due to aggregated protein inhibiting proteasomal function. This problem can be overcome if the sequestration of aggregated protein into inclusion bodies is enhanced. This model predicts responses to reactive oxygen species-mediated stress that are consistent with currently available experimental data. The model can be used to assess specific interventions to reduce cell death due to impaired protein homeostasis.  相似文献   

19.
20.
The ability of proteins to fold into complex three-dimensional shapes is truly amazing. Given the difficulty of the reaction it is perhaps unsurprising that many proteins in vivo are unable to fold correctly. These misfolded proteins are generally recognized by the cell's quality control machinery and dealt with through degradation. However in an increasing number of diseases, such as Huntington's, Alzheimer's and alpha1-antitrypsin deficiency, misfolded protein accumulates both within and outside the cell. This aggregated protein is able to evade the normal cellular responses and in some cases even disable it. In this review we present an overview of protein misfolding and examine recent data which is beginning to reveal the mechanisms by which protein aggregates are toxic to cells.  相似文献   

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