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1.
Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases associated with progressive oligo- and multimerization
of the prion protein (PrPC), its conformational conversion, aggregation and precipitation. We recently proposed that PrPC serves as a cell surface scaffold protein for a variety of signaling modules, the effects of which translate into wide-range
functional consequences. Here we review evidence for allosteric functions of PrPC, which constitute a common property of scaffold proteins. The available data suggest that allosteric effects among PrPC and its partners are involved in the assembly of multi-component signaling modules at the cell surface, impose upon both
physiological and pathological conformational responses of PrPC, and that allosteric dysfunction of PrPC has the potential to entail progressive signal corruption. These properties may be germane both to physiological roles of
PrPC, as well as to the pathogenesis of the TSEs and other degenerative/non-communicable diseases. 相似文献
2.
Olga Moreno-Gonzalo Irene Fernandez-Delgado Francisco Sanchez-Madrid 《Cellular and molecular life sciences : CMLS》2018,75(1):1-19
Extracellular vesicles (EVs) are released by cells to the extracellular environment to mediate inter-cellular communication. Proteins, lipids, nucleic acids and metabolites shuttled in these vesicles modulate specific functions in recipient cells. The enrichment of selected sets of proteins in EVs compared with global cellular levels suggests the existence of specific sorting mechanisms to specify EV loading. Diverse post-translational modifications (PTMs) of proteins participate in the loading of specific elements into EVs. In this review, we offer a perspective on PTMs found in EVs and discuss the specific role of some PTMs, specifically Ubiquitin and Ubiquitin-like modifiers, in exosomal sorting of protein components. The understanding of these mechanisms will provide new strategies for biomedical applications. Examples include the presence of defined PTM marks on EVs as novel biomarkers for the diagnosis and prognosis of certain diseases, or the specific import of immunogenic components into EVs for vaccine generation. 相似文献
3.
Didier Vilette Josquin Courte Jean Michel Peyrin Laurent Coudert Laurent Schaeffer Olivier Andréoletti Pascal Leblanc 《Cellular and molecular life sciences : CMLS》2018,75(14):2557-2574
Prions are infectious agents that cause fatal neurodegenerative diseases. Current evidence indicates that they are essentially composed of an abnormally folded protein (PrPSc). These abnormal aggregated PrPSc species multiply in infected cells by recruiting and converting the host PrPC protein into new PrPSc. How prions move from cell to cell and progressively spread across the infected tissue is of crucial importance and may provide experimental opportunity to delay the progression of the disease. In infected cells, different mechanisms have been identified, including release of infectious extracellular vesicles and intercellular transfer of PrPSc-containing organelles through tunneling nanotubes. These findings should allow manipulation of the intracellular trafficking events targeting PrPSc in these particular subcellular compartments to experimentally address the relative contribution of these mechanisms to in vivo prion pathogenesis. In addition, such information may prompt further experimental strategies to decipher the causal roles of protein misfolding and aggregation in other human neurodegenerative diseases. 相似文献
4.
Modulation of signal transduction through the cellular prion protein is linked to its incorporation in lipid rafts 总被引:3,自引:0,他引:3
Hugel B Martínez MC Kunzelmann C Blättler T Aguzzi A Freyssinet JM 《Cellular and molecular life sciences : CMLS》2004,61(23):2998-3007
Because expressed at a significant level at the membrane of human T cells, we made the hypothesis that the cellular prion protein (PrPc) could behave as a receptor, and be responsible for signal transduction. PrPc engagement by specific antibodies was observed to induce an increase in cytosolic calcium concentration and led to enhanced activity of Src protein tyrosine kinases. Antibodies to CD4 and CD59 did not influence calcium fluxes or signaling. The effect was maximal after the formation of a network involving avidin and biotinylated antibody to PrPc and was inhibited after raft disruption. PrPc localization was not restricted to rafts in resting cells but engagement was a prerequisite for signaling induction, with concomitant PrPc recruitment into rafts. These results suggest a role for PrPc in signaling pathways, and show that lateral redistribution of the protein into rafts is important for subsequent signal transduction.Received 22 July 2004; received after revision 10 September 2004; accepted 7 October 2004 相似文献
5.
Catherine Aude-Garcia Christian Villiers Serge M. Candéias Catherine Garrel Caroline Bertrand Véronique Collin Patrice N. Marche Evelyne Jouvin-Marche 《Cellular and molecular life sciences : CMLS》2011,68(4):687-696
The cellular prion glycoprotein (PrPC) is ubiquitously expressed but its physiologic functions remain enigmatic, particularly in the immune system. Here, we demonstrate
in vitro and in vivo that PrPC is involved in T lymphocytes response to oxidative stress. By monitoring the intracellular level of reduced glutathione,
we show that PrP−/− thymocytes display a higher susceptibility to H2O2 exposure than PrP+/+ cells. Furthermore, we find that in mice fed with a restricted diet, a regimen known to increase the intracellular level
of ROS, PrP−/− thymocytes are more sensitive to oxidative stress. PrPC function appears to be specific for oxidative stress, since no significant differences are observed between PrP−/− and PrP+/+ mice exposed to other kinds of stress. We also show a marked evolution of the redox status of T cells throughout differentiation
in the thymus. Taken together, our results clearly ascribe to PrPC a protective function in thymocytes against oxidative stress. 相似文献
6.
Mornon JP Prat K Dupuis F Boisset N Callebaut I 《Cellular and molecular life sciences : CMLS》2002,59(12):2144-2154
Prion diseases are neurodegenerative disorders associated with a conformational conversion of the prion PrP protein, in which
the β-strand content increases and that of the α helix decreases. However, the structure of the pathogenous form PrPSc, occurring after conformational conversion of the normal cellular form PrPC, is not yet known. From sequence analysis, we have previously proposed that helix H2 of the prion PrPC structure might be a key region for this structural conversion. More recently, we identified the TATA box-binding protein
fold as a putative scaffold that may locally satisfy the predicted secondary-structure organisation of PrPSc. In the present analysis, we detail the schematic construction of PrPSc monomeric and dimeric models, based on this hypothesis. These models are globally compatible with available data and therefore
may provide further insights into the structurally and functionally elusive PrP protein.
Some comments are also devoted to a comparison of the yeast Ure2p prion and animal prions.
Received 29 July 2002; received after revision 24 October 2002; accepted 24 October 2002
RID="*"
ID="*"Corresponding author. 相似文献
7.
Reuter A Binkle U Stuermer CA Plattner H 《Cellular and molecular life sciences : CMLS》2004,61(16):2092-2099
A new model of caveolin association with lipid body cores has recently been proposed which may be relevant to a number of cellular processes, e.g. lipid body generation. Here we show that PrPc and reggie-1 and reggie-2 also occur in the cores of Nile Red/Bodipy-stained (neutral lipid-containing) vesicular structures and, in immunoblots, in the lipid-enriched fraction after density gradient centrifugation. These lipid-rich vesicles increase in number following cell feeding with oleic acid, differ from early endosome antigen 1- and Lamp-2-positive endosomes/lysosomes, exhibit an opaque content and lack surrounding actin staining. Our results suggest that the content of these vesicles, together with reggie-1 and -2 and PrPc, is expelled.Received 3 May 2004; received after revision 14 June 2004; accepted 23 June 2004 相似文献
8.
Birke J. Benedikter Antje R. Weseler Emiel F. M. Wouters Paul H. M. Savelkoul Gernot G. U. Rohde Frank R. M. Stassen 《Cellular and molecular life sciences : CMLS》2018,75(13):2321-2337
Extracellular vesicles (EVs), including microvesicles and exosomes, are emerging as important regulators of homeostasis and pathophysiology. During pro-inflammatory and pro-oxidant conditions, EV release is induced. As EVs released under such conditions often exert pro-inflammatory and procoagulant effects, they may actively promote the pathogenesis of chronic diseases. There is evidence that thiol group-containing antioxidants can prevent EV induction by pro-inflammatory and oxidative stimuli, likely by protecting protein thiols of the EV-secreting cells from oxidation. As the redox state of protein thiols greatly impacts three-dimensional protein structure and, consequently, function, redox modifications of protein thiols may directly modulate EV release in response to changes in the cell’s redox environment. In this review article, we discuss targets of redox-dependent thiol modifications that are known or expected to be involved in the regulation of EV release, namely redox-sensitive calcium channels, N-ethylmaleimide sensitive factor, protein disulfide isomerase, phospholipid flippases, actin filaments, calpains and cell surface-exposed thiols. Thiol protection is proposed as a strategy for preventing detrimental changes in EV signaling in response to inflammation and oxidative stress. Identification of the thiol-containing proteins that modulate EV release in pro-oxidant environments could provide a rationale for broad application of thiol group-containing antioxidants in chronic inflammatory diseases. 相似文献
9.
Yu Yamaguchi Eiko Sakai Kuniaki Okamoto Hiroshi Kajiya Koji Okabe Mariko Naito Tomoko Kadowaki Takayuki Tsukuba 《Cellular and molecular life sciences : CMLS》2018,75(1):33-48
Rab44 is an atypical Rab GTPase that contains some additional domains such as the EF-hand and coiled-coil domains as well as Rab-GTPase domain. Although Rab44 genes have been found in mammalian genomes, no studies concerning Rab44 have been reported yet. Here, we identified Rab44 as an upregulated protein during osteoclast differentiation. Knockdown of Rab44 by small interfering RNA promotes RANKL-induced osteoclast differentiation of the murine monocytic cell line, RAW-D or of bone marrow-derived macrophages (BMMs). In contrast, overexpression of Rab44 prevents osteoclast differentiation. Rab44 was localized in the Golgi complex and lysosomes, and Rab44 overexpression caused an enlargement of early endosomes. A series of deletion mutant studies of Rab44 showed that the coiled-coil domain and lipidation sites of Rab44 is important for regulation of osteoclast differentiation. Mechanistically, Rab44 affects nuclear factor of activated T-cells c1 (NFATc1) signaling in RANKL-stimulated macrophages. Moreover, Rab44 depletion caused an elevation in intracellular Ca2+ transients upon RANKL stimulation, and particularly regulated lysosomal Ca2+ influx. Taken together, these results suggest that Rab44 negatively regulates osteoclast differentiation by modulating intracellular Ca2+ levels followed by NFATc1 activation. 相似文献
10.
Sabine Gilch Christian Bach Gloria Lutzny Ina Vorberg Hermann M. Schätzl 《Cellular and molecular life sciences : CMLS》2009,66(24):3979-3991
The infectious agent in prion diseases consists of an aberrantly folded isoform of the cellular prion protein (PrPc), termed PrPSc, which accumulates in brains of affected individuals. Studies on prion-infected cultured cells indicate that cellular cholesterol
homeostasis influences PrPSc propagation. Here, we demonstrate that the cellular PrPSc content decreases upon accumulation of cholesterol in late endosomes, as induced by NPC-1 knock-down or treatment with U18666A.
PrPc trafficking, lipid raft association, and membrane turnover are not significantly altered by such treatments. Cellular PrPSc formation is not impaired, suggesting that PrPSc degradation is increased by intracellular cholesterol accumulation. Interestingly, PrPSc propagation in U18666A-treated cells was partially restored by overexpression of rab 9, which causes redistribution of cholesterol
and possibly of PrPSc to the trans-Golgi network. Surprisingly, rab 9 overexpression itself reduced cellular PrPSc content, indicating that PrPSc production is highly sensitive to alterations in dynamics of vesicle trafficking. 相似文献
11.
Q.-Q. Li X.-X. Cao J.-D. Xu Q. Chen W.-J. Wang F. Tang Z.-Q. Chen X.-P. Liu Z.-D. Xu 《Cellular and molecular life sciences : CMLS》2009,66(3):504-515
We previously reported that treatment with P-glycoprotein (P-gp) substrates promotes in vitro invasion in multidrug-resistant (MDR) breast cancer cells. This effect is initiated by the P-gp pump function and mediated
by interaction of P-gp with some unknown component(s). However, the underlying mechanism(s) remains poorly understood. Here
we confirm a novel physical interaction between P-gp and cellular prion protein (PrPc). Blocking P-gp activity or depletion of PrPc inhibited paclitaxel (P-gp substrate)- induced invasion. Paclitaxel further facilitated the formation of P-gp/PrPc clusters residing in caveolar domains and promoted the association of P-gp with caveolin-1. Both caveolin-1 and the integrity
of caveolae were required for the drug-induced invasion. In addition, the P-gp/PrPc complex also played an important role in anti-apoptotic activity of MCF7/Adr cells.These data provide new insights into the
mode by which MDR breast cancers evade cytotoxic attacks from P-gp substrates and also suggest a role for P-gp/ PrPc interaction in this process.
Received 4 September 2008; received after revision 16 November 2008; accepted 18 November 2008 相似文献
12.
Yuan J Dong Z Guo JP McGeehan J Xiao X Wang J Cali I McGeer PL Cashman NR Bessen R Surewicz WK Kneale G Petersen RB Gambetti P Zou WQ 《Cellular and molecular life sciences : CMLS》2008,65(4):631-643
Human prion diseases are characterized by the accumulation in the brain of proteinase K (PK)-resistant prion protein designated
PrP27 – 30 detectable by the 3F4 antibody against human PrP109 – 112. We recently identified a new PK-resistant PrP species,
designated PrP*20, in uninfected human and animal brains. It was preferentially detected with the 1E4 antibody against human PrP 97 – 108 but
not with the anti-PrP 3F4 antibody, although the 3F4 epitope is adjacent to the 1E4 epitope in the PrP*20 molecule. The present study reveals that removal of the N-terminal amino acids up to residue 91 significantly increases accessibility
of the 1E4 antibody to PrP of brains and cultured cells. In contrast to cells expressing wild-type PrP, cells expressing pathogenic
mutant PrP accumulate not only PrP*20 but also a small amount of 3F4-detected PK-resistant PrP27 – 30. Remarkably, during the course of human prion disease, a
transition from an increase in 1E4-detected PrP*20 to the occurrence of the 3F4-detected PrP27 – 30 was observed. Our study suggests that an increase in the level of PrP*20 characterizes the early stages of prion diseases.
Received 17 October 2007; received after revision 5 December 2007; accepted 14 December 2007 相似文献
13.
Géza Tamás Szabó Bettina Tarr Krisztina Pálóczi Katalin Éder Eszter Lajkó Ágnes Kittel Sára Tóth Bence György Mária Pásztói Andrea Németh Xabier Osteikoetxea Éva Pállinger András Falus Katalin Szabó-Taylor Edit Irén Buzás 《Cellular and molecular life sciences : CMLS》2014,71(20):4055-4067
Under physiological and pathological conditions, extracellular vesicles (EVs) are present in the extracellular compartment simultaneously with soluble mediators. We hypothesized that cytokine effects may be modulated by EVs, the recently recognized conveyors of intercellular messages. In order to test this hypothesis, human monocyte cells were incubated with CCRF acute lymphoblastic leukemia cell line-derived EVs with or without the addition of recombinant human TNF, and global gene expression changes were analyzed. EVs alone regulated the expression of numerous genes related to inflammation and signaling. In combination, the effects of EVs and TNF were additive, antagonistic, or independent. The differential effects of EVs and TNF or their simultaneous presence were also validated by Taqman assays and ELISA, and by testing different populations of purified EVs. In the case of the paramount chemokine IL-8, we were able to demonstrate a synergistic upregulation by purified EVs and TNF. Our data suggest that neglecting the modulating role of EVs on the effects of soluble mediators may skew experimental results. On the other hand, considering the combined effects of cytokines and EVs may prove therapeutically useful by targeting both compartments at the same time. 相似文献
14.
Iva Hafner-Bratkovi? Mojca Ben?ina Katherine A. Fitzgerald Douglas Golenbock Roman Jerala 《Cellular and molecular life sciences : CMLS》2012,69(24):4215-4228
Prion diseases are fatal transmissible neurodegenerative diseases, characterized by aggregation of the pathological form of prion protein, spongiform degeneration, and neuronal loss, and activation of astrocytes and microglia. Microglia can clear prion plaques, but on the other hand cause neuronal death via release of neurotoxic species. Elevated expression of the proinflammatory cytokine IL-1β has been observed in brains affected by several prion diseases, and IL-1R-deficiency significantly prolonged the onset of the neurodegeneration in mice. We show that microglial cells stimulated by prion protein (PrP) fibrils induced neuronal toxicity. Microglia and macrophages release IL-1β upon stimulation by PrP fibrils, which depends on the NLRP3 inflammasome. Activation of NLRP3 inflammasome by PrP fibrils requires depletion of intracellular K+, and requires phagocytosis of PrP fibrils and consecutive lysosome destabilization. Among the well-defined molecular forms of PrP, the strongest NLRP3 activation was observed by fibrils, followed by aggregates, while neither native monomeric nor oligomeric PrP were able to activate the NLRP3 inflammasome. Our results together with previous studies on IL-1R-deficient mice suggest the IL-1 signaling pathway as the perspective target for the therapy of prion disease. 相似文献
15.
Silvia Lisa Massimiliano Meli Gema Cabello Ruth Gabizon Giorgio Colombo María Gasset 《Cellular and molecular life sciences : CMLS》2010,67(16):2825-2838
The conversion of the cellular prion protein (PrPC) into its disease-associated form (PrPSc) involves a major conformational change and the accumulation of sulfoxidized methionines. Computational and synthetic approaches
have shown that this change in the polarity of M206 and M213 impacts the C-terminal domain native α-fold allowing the flexibility
required for the structural conversion. To test the effect in the full-length molecule with site-specificity, we have generated
M-to-S mutations. Molecular dynamics simulations show that the replacement indeed perturbs the native state. When this mutation
is placed at the conserved methionines of HaPrP(23–231), only substitutions at the Helix-3 impair the α-fold, stabilizing
a non-native state with perturbed secondary structure, loss of native tertiary contacts, increased surface hydrophobicity,
reduced thermal stability and an enhanced tendency to aggregate into protofibrillar polymers. Our work supports that M206
and M213 function as α-fold gatekeepers and suggests that their redox state regulate misfolding routes. 相似文献
16.
Nasibeh Karimi Aleksander Cvjetkovic Su Chul Jang Rossella Crescitelli Mohammad Ali Hosseinpour Feizi Rienk Nieuwland Jan Lötvall Cecilia Lässer 《Cellular and molecular life sciences : CMLS》2018,75(15):2873-2886
The isolation of extracellular vesicles (EVs) from blood is of great importance to understand the biological role of circulating EVs and to develop EVs as biomarkers of disease. Due to the concurrent presence of lipoprotein particles, however, blood is one of the most difficult body fluids to isolate EVs from. The aim of this study was to develop a robust method to isolate and characterise EVs from blood with minimal contamination by plasma proteins and lipoprotein particles. Plasma and serum were collected from healthy subjects, and EVs were isolated by size-exclusion chromatography (SEC), with most particles being present in fractions 8–12, while the bulk of the plasma proteins was present in fractions 11–28. Vesicle markers peaked in fractions 7–11; however, the same fractions also contained lipoprotein particles. The purity of EVs was improved by combining a density cushion with SEC to further separate lipoprotein particles from the vesicles, which reduced the contamination of lipoprotein particles by 100-fold. Using this novel isolation procedure, a total of 1187 proteins were identified in plasma EVs by mass spectrometry, of which several proteins are known as EV-associated proteins but have hitherto not been identified in the previous proteomic studies of plasma EVs. This study shows that SEC alone is unable to completely separate plasma EVs from lipoprotein particles. However, combining SEC with a density cushion significantly improved the separation of EVs from lipoproteins and allowed for a detailed analysis of the proteome of plasma EVs, thus making blood a viable source for EV biomarker discovery. 相似文献
17.
18.
Di Cesare A Del Piccolo P Zacchetti D Grohovaz F 《Cellular and molecular life sciences : CMLS》2006,63(21):2546-2553
Astrocytes are a heterogeneous population of cells that are endowed with a great variety of receptors for neurotransmitters
and neuromodulators. Recently prostaglandin E2 has attracted great interest since it is not only released by astrocytes but also activates receptors coupled to either phospholipase
C or adenylyl cyclase. We report that EP2 receptor stimulation triggers cAMP production but also causes release of Ca2+ from intracellular stores. This effect is shared by other receptors similarly coupled to adenylyl cyclase and elicited by
direct stimulation of the enzyme or application of cAMP analogues. However, the stimulation of the Ca2+ response by cAMP is not mediated by protein kinase A, since a specific antagonist of this kinase had no effect. Such a cross-talk
between cAMP and Ca2+ was not observed in all astrocytes. It might therefore reflect a specific resource of either a subpopulation or astrocytes
in a specific functional state.
Received 6 June 2006; received after revision 25 July 2006; accepted 31 August 2006 相似文献
19.
Prion diseases are fatal neurodegenerative and infectious disorders of humans and animals, characterized by structural transition
of the host-encoded cellular prion protein (PrPc) into the aberrantly folded pathologic isoform PrPSc. RNA, DNA or peptide aptamers are classes of molecules which can be selected from complex combinatorial libraries for high
affinity and specific binding to prion proteins and which might therefore be useful in diagnosis and therapy of prion diseases.
Nucleic acid aptamers, which can be chemically synthesized, stabilized and immobilized, appear more suitable for diagnostic
purposes, allowing use of PrPSc as selection target. Peptide aptamers facilitate appropriate intracellular expression, targeting and re-routing without losing
their binding properties to PrP, a requirement for potential therapeutic gene transfer experiments in vivo. Elucidation of
structural properties of peptide aptamers might be used as basis for rational drug design, providing another attractive application
of peptide aptamers in the search for effective anti-prion strategies. 相似文献
20.
Beatriz Domingo María Gasset Mario Durán-Prado Justo P. Castaño Antonio Serrano Thierry Fischer Juan Llopis 《Cellular and molecular life sciences : CMLS》2010,67(19):3345-3354
Membrane protein function is determined by the relative organization of the protein domains with respect to the membrane.
We have experimentally verified the topology of a protein with diverse orientations arising from a single primary sequence
(the cellular prion protein, PrPC), a novel somatostatin truncated receptor, and the Golgi-associated protein GPBP91. Tagging with fluorescent proteins (FP) allows location of their expression at the plasma membrane or at endomembranes, but
does not inform about their orientation. Exploiting the pH dependency of some FPs, we developed a pH exchange assay in which
extracellularly exposed FPs are quenched by application of low pH buffer. We constructed standards to demonstrate and calibrate
the assay, and the method was adapted for acidic organelle membrane proteins. This method can serve as a proof of concept,
experimentally confirming and/or discriminating in living cells among theoretical topology predictions, providing the proportion
of inside/outside orientation for proteins with multiple forms. 相似文献