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71.
Jennifer A. Johnston Cristina L. Ward Ron R. Kopito 《The Journal of cell biology》1998,143(7):1883-1898
Intracellular deposition of misfolded protein aggregates into ubiquitin-rich cytoplasmic inclusions is linked to the pathogenesis of many diseases. Why these aggregates form despite the existence of cellular machinery to recognize and degrade misfolded protein and how they are delivered to cytoplasmic inclusions are not known. We have investigated the intracellular fate of cystic fibrosis transmembrane conductance regulator (CFTR), an inefficiently folded integral membrane protein which is degraded by the cytoplasmic ubiquitin-proteasome pathway. Overexpression or inhibition of proteasome activity in transfected human embryonic kidney or Chinese hamster ovary cells led to the accumulation of stable, high molecular weight, detergent-insoluble, multiubiquitinated forms of CFTR. Using immunofluorescence and transmission electron microscopy with immunogold labeling, we demonstrate that undegraded CFTR molecules accumulate at a distinct pericentriolar structure which we have termed the aggresome. Aggresome formation is accompanied by redistribution of the intermediate filament protein vimentin to form a cage surrounding a pericentriolar core of aggregated, ubiquitinated protein. Disruption of microtubules blocks the formation of aggresomes. Similarly, inhibition of proteasome function also prevented the degradation of unassembled presenilin-1 molecules leading to their aggregation and deposition in aggresomes. These data lead us to propose that aggresome formation is a general response of cells which occurs when the capacity of the proteasome is exceeded by the production of aggregation-prone misfolded proteins. 相似文献
72.
Histiostoma papillata sp. n. (Acari: Histiostomatidae) is described from Victoria, Australia. It was found in the fins and gills of juvenile Murray cod, Maccullochella peelii peelii (Mitchell), where it appeared to inflict injuries thought to be responsible for the mortality of fish in a diet trial. 相似文献
73.
M A Harrington K L Gunderson R R Kopito 《The Journal of biological chemistry》1999,274(39):27536-27544
Gating of the cystic fibrosis Cl(-) channel requires hydrolysis of ATP by its nucleotide binding folds, but how this process controls the kinetics of channel gating is poorly understood. In the present work we show that the kinetics of channel gating and presumably the rate of ATP hydrolysis depends on the species of divalent cation present and the oxidation state of the protein. With Ca(2+) as the dominant divalent cation instead of Mg(2+), the open burst duration of the channel is increased approximately 20-fold, and this change is reversible upon washout of Ca(2+). In contrast, "soft" divalent cations such as Cd(2+) interact covalently with cystic fibrosis transmembrane conductance regulator (CFTR). These metals decrease both opening and closing rates of the channel, and the effects are not reversed by washout. Oxidation of CFTR channels with a variety of oxidants resulted in a similar slowing of channel gating. In contrast, reducing agents had the opposite effect, increasing both opening and closing rates of the channel. In cell-attached patches, CFTR channels exhibit both oxidized and reduced types of gating, raising the possibility that regulation of the redox state of the channel may be a physiological mode of control of CFTR channel activity. 相似文献
74.
The inherited retinal degenerations are typified by retinitis pigmentosa (RP), a heterogeneous group of inherited disorders that causes the destruction of photoreceptor cells, the retinal pigmented epithelium, and choroid. This group of blinding conditions affects over 1.5 million persons worldwide. Approximately 30-40% of human autosomal dominant (AD) RP is caused by dominantly inherited missense mutations in the rhodopsin gene. Here we show that P23H, the most frequent RP mutation in American patients, renders rhodopsin extremely prone to form high molecular weight oligomeric species in the cytoplasm of transfected cells. Aggregated P23H accumulates in aggresomes, which are pericentriolar inclusion bodies that require an intact microtubule cytoskeleton to form. Using fluorescence resonance energy transfer (FRET), we observe that P23H aggregates in the cytoplasm even at extremely low expression levels. Our data show that the P23H mutation destabilizes the protein and targets it for degradation by the ubiquitin proteasome system. P23H is stabilized by proteasome inhibitors and by co-expression of a dominant negative form of ubiquitin. We show that expression of P23H, but not wild-type rhodopsin, results in a generalized impairment of the ubiquitin proteasome system, suggesting a mechanism for photoreceptor degeneration that links RP to a broad class of neurodegenerative diseases. 相似文献
75.
Kopito RR 《Molecular cell》2003,12(6):1349-1351
Molecular motors are the long-haul carriers of eukaryotic cells, moving cargos bidirectionally along microtubule tracks. In the December 12th issue of Cell, report that HDAC6, a tubulin deacetylase, functions as an adaptor that links cargos of aggregated protein to the minus end-directed motor, cytoplasmic dynein. 相似文献
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Piyali Sabui Sadhucharan Mallick Kshitij RB Singh Arunadevi Natarajan Ranjana Verma Jay Singh Ravindra Pratap Singh 《Luminescence》2023,38(7):1047-1063
Food safety and quality are among the most significant and prevalent research areas worldwide. The fabrication of appropriate technical procedures or devices for the recognition of hazardous features in foods is essential to safeguard food materials. In the recent era, developing high-performance sensors based on carbon nanomaterial for food safety investigation has made noteworthy progress. Hence this review briefly highlights the different detection approaches (colorimetric sensor, fluorescence sensor, surface-enhanced Raman scattering, surface plasmon resonance, chemiluminescence, and electroluminescence), functional carbon nanomaterials with various dimensions (quantum dots, graphene quantum dots) and detection mechanisms. Further, this review emphasizes the assimilation of carbon nanomaterials with optical sensors to identify multiple contaminants in food products. The insights of carbon-based nanomaterials optical sensors for pesticides and insecticides, toxic metals, antibiotics, microorganisms, and mycotoxins detection are described in detail. Finally, the opportunities and future perspectives of nanomaterials-based optical analytical approaches for detecting various food contaminants are discussed. 相似文献
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