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1.
Intracellular deposits of aggregated alpha-synuclein are a hallmark of Parkinson’s disease. Protein–protein interactions are
critical in the regulation of cell proteostasis. Synphilin-1 interacts both in vitro and in vivo with alpha-synuclein promoting
its aggregation. We report here that synphilin-1 specifically inhibits the degradation of alpha-synuclein wild-type and its
missense mutants by the 20S proteasome due at least in part by the interaction of the ankyrin and coiled-coil domains of synphilin-1
(amino acids 331–555) with the N-terminal region (amino acids 1–60) of alpha-synuclein. Co-expression of synphilin-1 and alpha-synuclein
wild-type in HeLa and N2A cells produces a specific increase in the half-life of alpha-synuclein, as degradation of unstable
fluorescent reporters is not affected. Synphilin-1 inhibition can be relieved by co-expression of Siah-1 that targets synphilin-1
to degradation. Synphilin-1 inhibition of the proteasomal pathway of degradation of alpha-synuclein may help to understand
the pathophysiological changes occurring in PD and other synucleinopathies. 相似文献
2.
4-Hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer's disease 总被引:3,自引:0,他引:3
Shringarpure R Grune T Sitte N Davies KJ 《Cellular and molecular life sciences : CMLS》2000,57(12):1802-1809
The amyloid β-peptide (Aβ) is a 4-kDa species derived from the amyloid precursor protein, which accumulates in the brains of patients with Alzheimer’s
disease. Although we lack full understanding of the etiology and pathogenesis of selective neuron death, considerable data
do imply roles for both the toxic Aβ and increased oxidative stress. Another significant observation is the accumulation of abnormal, ubiquitin-conjugated proteins
in affected neurons, suggesting dysfunction of the proteasome proteolytic system in these cells. Recent reports have indicated
that Aβ can bind and inhibit the proteasome, the major cytoslic protease for degrading damaged and ubiquitin-conjugated proteins.
Earlier results from our laboratory showed that moderately oxidized proteins are preferentially recognized and degraded by
the proteasome; however, severely oxidized proteins cannot be easily degraded and, instead, inhibit the proteasome. We hypothesized
that oxidatively modified Aβ might have a stronger (or weaker) inhibitory effect on the proteasome than does native Aβ. We therefore also investigated the proteasome inhibitory action of Aβ
1–40 (a peptide comprising the first 40 residues of Aβ) modified by the intracellular oxidant hydrogen peroxide, and by the lipid peroxidation product 4-hydroxynonenal (HNE). H2O2 modification of Aβ
1–40 generates a progressively poorer inhibitor of the purified human 20S proteasome. In contrast, HNE modification of Aβ
1–40 generates a progressively more selective and efficient inhibitor of the degradation of fluorogenic peptides and oxidized
protein substrates by human 20S proteasome. This interaction may contribute to certain pathological manifestations of Alzheimer’s
disease
Received 26 September 2000; accepted 26 September 2000 相似文献
3.
Molecular mechanisms of nitrosative stress-mediated protein misfolding in neurodegenerative diseases
Nitrosative and oxidative stress, associated with the generation of excessive reactive oxygen or nitrogen species, are thought
to contribute to neurodegenerative disorders. Many such diseases are characterized by conformational changes in proteins that
result in their misfolding and aggregation. Accumulating evidence implies that at least two pathways affect protein folding:
the ubiquitin-proteasome system (UPS) and molecular chaperones. Normal protein degradation by the UPS can prevent accumulation
of aberrantly folded proteins. Molecular chaperones – such as protein-disulfide isomerase, glucose-regulated protein 78, and
heat shock proteins – can provide neuroprotection from aberrant proteins by facilitating proper folding and thus preventing
their aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Here,
we present evidence for the hypothesis that nitric oxide contributes to degenerative conditions by S-nitrosylating specific chaperones or UPS proteins that would otherwise prevent accumulation of misfolded proteins.
Received 5 December 2006; received after revision 7 February 2007; accepted 15 March 2007 相似文献
4.
Amyloid β-induced FOXRED2 mediates neuronal cell death via inhibition of proteasome activity 总被引:1,自引:1,他引:0
Proteasome inhibition has been regarded as one of the mediators of Aβ neurotoxicity. In this study, we found that FOXRED2,
a novel endoplasmic reticulum (ER) residential protein, is highly up-regulated by Aβ in rat cortical neurons and SH-SY5Y cells.
Over-expression of FOXRED2 inhibits proteasome activity in the microsomal fractions containing ER and interferes with proteasome
assembly, as evidenced by gel filtration and native gel electrophoresis analysis. In contrast, reduced expression of FOXRED2
rescues Aβ-induced inhibition of proteasome activity. FOXRED2 is an unstable protein with two degradation boxes and one KEN
box, and its N-terminal oxidoreductase domain is required for proteasome inhibition. Ectopic expression of FOXRED2 induces
ER stress-mediated cell death via caspase-12, which is inhibited by Salubrinal. Further, down-regulation of FOXRED2 expression
attenuates Aβ-induced cell death and the ER stress response. These results suggest that up-regulated FOXRED2 inhibits proteasome
activity by interfering with 26S proteasome assembly to contribute to Aβ neurotoxicity via an ER stress response. 相似文献
5.
Differential use of an in-frame translation initiation codon regulates human mu opioid receptor (OPRM1) 总被引:1,自引:1,他引:0
Kyu Young Song Hack Sun Choi Cheol Kyu Hwang Chun Sung Kim Ping-Yee Law Li-Na Wei Horace H. Loh 《Cellular and molecular life sciences : CMLS》2009,66(17):2933-2942
The pharmacological effects of morphine and morphine-like drugs are mediated primarily through the μ opioid receptor. Here
we show that differential use of an in-frame translational start codon in the 5′-untranslated region of the OPRM1 generates
different translational products in vivo and in vitro. The 5′-end of the OPRM1 gene is necessary for initiating the alternate
form and for subsequent degradation of the protein. Initiation of OPRM1 at the upstream site decreases the initiation at the
main AUG site. However, alternative initiation of the long form of OPRM1 produces a protein with a short half-life, resulting
from degradation mediated by the ubiquitin–proteasome pathway. Reporter and degradation assays showed that mutations of this
long form at the second and third lysines reduce ubiquitin-dependent proteasome degradation, stabilizing the protein. The
data suggest that MOP expression is controlled in part by initiation of the long form of MOP at the alternate site. 相似文献
6.
REGγ, a proteasome activator and beyond? 总被引:1,自引:0,他引:1
REGγ, a member of the 11S proteasome activators, has been shown to bind and activate the 20S proteasome to promote proteasome-dependent
degradation of important regulatory proteins, such as SRC-3 and cyclin-dependent kinase inhibitors p21, p16, and p19, in a
ubiquitin- and ATP-independent manner. Furthermore, REGγ has been shown to facilitate the turnover of tumor suppressor p53
by promoting MDM2-mediated p53 ubiquitination. The discovery that REGγ regulates cell-cycle regulators is consistent with
previous studies where REGγ-deficient mice have shown retardation in body growth, decreased cell proliferation and increased
apoptosis, indicating a potential role of REGγ in cancer development. Additionally, REGγ’s ability to promote viral protein
degradation suggests its involvement in viral pathogenesis. This review presents an overview of the function of REGγ, a summary
of the current literature, and insight into the possible biological function of REGγ relating to cancer, viral pathogenesis,
and other diseases. 相似文献
7.
The role of the proteasome in the generation of MHC class I ligands and immune responses 总被引:2,自引:2,他引:0
The ubiquitin–proteasome system (UPS) degrades intracellular proteins into peptide fragments that can be presented by major
histocompatibility complex (MHC) class I molecules. While the UPS is functional in all mammalian cells, its subunit composition
differs depending on cell type and stimuli received. Thus, cells of the hematopoietic lineage and cells exposed to (pro)inflammatory
cytokines express three proteasome immunosubunits, which form the catalytic centers of immunoproteasomes, and the proteasome
activator PA28. Cortical thymic epithelial cells express a thymus-specific proteasome subunit that induces the assembly of
thymoproteasomes. We here review new developments regarding the role of these different proteasome components in MHC class
I antigen processing, T cell repertoire selection and CD8 T cell responses. We further discuss recently discovered functions
of proteasomes in peptide splicing, lymphocyte survival and the regulation of cytokine production and inflammatory responses. 相似文献
8.
Stress proteins in neural cells: functional roles in health and disease 总被引:11,自引:0,他引:11
Heat shock proteins (HSPs) or stress proteins participate in protein synthesis, protein folding, transport and translocalization processes. Stress situations trigger a heat shock response leading to their induction. Similarly, they can be upregulated by impairment of the proteasomal degradation pathway. The upregulation of stress proteins is an important step in prevention of protein aggregation and misfolding after stress, and also is essential during development and differentiation. A number of HSPs are constitutively or inducibly expressed in the nervous system and connected to protection of nerve cells and glia. The cytoskeleton is affected by stress, and HSPs have been shown to interact with the cytoskeleton in normal cells and to assist proper assembly, spatial organization and cross-linking properties. The integrity of the cytoskeleton is disturbed in many neurodegenerative disorders, and filamentous cytoplasmic inclusion bodies, containing a variety of HSPs, are observed. This review summarizes the recent literature on the presence and induction of HSPs in neural cells, and their possible functional roles in health and disease are discussed. 相似文献
9.
In eukaryotic cells, proteasomes are highly conserved protease complexes and eliminate unwanted proteins which are marked by poly-ubiquitin chains for degradation. The 26S proteasome consists of the proteolytic core particle, the 20S proteasome, and the 19S regulatory particle, which are composed of 14 and 19 different subunits, respectively. Proteasomes are the second-most abundant protein complexes and are continuously assembled from inactive precursor complexes in proliferating cells. The modular concept of proteasome assembly was recognized in prokaryotic ancestors and applies to eukaryotic successors. The efficiency and fidelity of eukaryotic proteasome assembly is achieved by several proteasome-dedicated chaperones that initiate subunit incorporation and control the quality of proteasome assemblies by transiently interacting with proteasome precursors. It is important to understand the mechanism of proteasome assembly as the proteasome has key functions in the turnover of short-lived proteins regulating diverse biological processes. 相似文献
10.
Hilt W 《Cellular and molecular life sciences : CMLS》2004,61(13):1615-1632
11.
Hyaluronan synthesis and degradation in cartilage and bone 总被引:1,自引:0,他引:1
Bastow ER Byers S Golub SB Clarkin CE Pitsillides AA Fosang AJ 《Cellular and molecular life sciences : CMLS》2008,65(3):395-413
Hyaluronan (HA) is a large but simple glycosaminoglycan composed of repeating D-glucuronic acid, β1–3 linked to N-acetyl-D-glucosamine β1–4, found in body fluids and tissues, in both intra- and extracellular compartments. Despite its structural
simplicity, HA has diverse functions in skeletal biology. In development, HA-rich matrices facilitate migration and condensation
of mesenchymal cells, and HA participates in joint cavity formation and longitudinal bone growth. In adult cartilage, HA binding
to aggrecan immobilises aggrecan, retaining it at the high concentrations required for compressive resilience. HA also appears
to regulate bone remodelling by controlling osteoclast, osteoblast and osteocyte behaviour. The functions of HA depend on
its intrinsic properties, which in turn rely on the degree of polymerisation by HA synthases, depolymerisation by hyaluronidases,
and interactions with HA-binding proteins. HA synthesis and degradation are closely regulated in skeletal tissues and aberrant
synthetic or degradative activity causes disease. The role and regulation of HA synthesis and degradation in cartilage, bone
and skeletal development is discussed.
Received 5 August 2007; received after revision 19 September 2007; accepted 20 September 2007 相似文献
12.
The 26S proteasome is the multi-protein protease that recognizes and degrades ubiquitinylated substrates targeted for destruction by the ubiquitin pathway. In addition to the well-documented subunit organization of the 26S holoenzyme, it is clear that a number of other proteins transiently associate with the 26S complex. These transiently associated proteins confer a number of different roles such as substrate presentation, cleavage of the multi-ubiquitin chain from the protein substrate and turnover of misfolded proteins. Such activities are essential for the 26S proteasome to efficiently fulfill its intracellular function in protein degradation. 相似文献
13.
Jean-Baptiste G Yang Z Greenwood MT 《Cellular and molecular life sciences : CMLS》2006,63(17):1969-1985
Regulator of G-Protein Signaling (RGS) refers to a conserved 120–125 amino acid motif that was first identified by its ability
to negatively regulate G-Protein-Coupled Receptor (GPCR) signalling. Mechanistically, RGSs were found to regulate GPCR responses
by binding to and stimulating the GTPase activity of the receptor-activated GTP-bound G α subunits. There are now over 25
mammalian RGSs containing proteins that are reported to carry out a variety of functions, many of which are unrelated to GPCR
signalling. RGS proteins range in size from small proteins that contain little more than an RGS box to very large proteins
that contain a variety of domains. The selectivity of function of the RGS proteins is attributable to the divergence of the
RGS sequences as well as the presence of a variety of functional motifs, which allow them to interact with other proteins.
Here we focus on the RGSs that are involved in modulating GPCR signalling by reviewing the diversity of the mechanisms involved
in regulating these RGSs.
Received 9 February 2006; received after revision 4 May 2006; accepted 22 May 2006 相似文献
14.
In renal carcinoma cells (RCC4) hypoxia inducible factor-1 (HIF-1) is constitutively expressed due to a von Hippel Lindau
protein deficiency, but can be degraded by calpain, independently of the 26S proteasome, when exposed to hypoxia/nitric oxide
(NO). In this study we examined molecular mechanisms to explain calpain activation. The inability of hypoxia/NO to degrade
HIF-1α in respiratory-deficient RCC4-ρ0 cells pointed to the requirement for mitochondria-derived reactive oxygen species.
A prerequisite for O
2
−
in combination with NO to destabilize HIF-1α was corroborated in RCC4-p0 cells, when the redox cycler 2,3-dimethoxy-1,4-naphthoquinone
was used as a source of superoxide. Degradation of HIF-1α required intracellular calcium transients and calpain activation.
Using uric acid to interfere with signal transmission elicited by NO/O
2
−
blocked HIF-1α degradation and attenuated a calcium increase. We conclude that an oxidative signal as a result of NO/O
2
−
coformation triggers a calcium increase that activates calpain to degrade HIF-1α, independently of the proteasome.
Received 14 August 2007; received after revision 4 October 2007; accepted 22 October 2007 相似文献
15.
Regulation of transcription factors by protein degradation 总被引:4,自引:0,他引:4
16.
Wójcik C 《Cellular and molecular life sciences : CMLS》1999,56(11-12):908-917
The proteasome (multicatalytic proteinase complex, prosome) is a major cytoplasmic proteolytic enzyme, responsible for degradation of the vast majority of intracellular proteins. Proteins degraded by the proteasome are usually tagged with multiple ubiquitin moieties, conjugated to the substrates by a complicated cascade of enzymes. Over the last years, evidence has accumulated that changes in the expression and activity of the different components of the ubiquitin-proteasome system occur during apoptosis. Proteasome inhibitors have been used to induce apoptosis in various cell types, whereas in others, these compounds were able to prevent apoptosis induced by different stimuli. The proteasome mediated step(s) in apoptosis is located upstream of mitochondrial changes and caspase activation, and can involve in different systems Bcl-2, Jun N-terminal kinase, heat shock proteins, Myc, p53, polyamines and other factors. 相似文献
17.
Gemma Olmos María I. Arenas Raquel Bienes María Jose Calzada Julián Aragonés Maria Laura Garcia-Bermejo Manuel O. Landazuri Javier Lucio-Cazaña 《Cellular and molecular life sciences : CMLS》2009,66(13):2167-2180
Hypoxia-inducible factor-1α (HIF-1α) protein is degraded under normoxia by its association to von Hippel-Lindau protein (pVHL)
and further proteasomal digestion. However, human renal cells HK-2 treated with 15-deoxy-Δ12,14-prostaglandin-J2 (15d-PGJ2) accumulate HIF-1α in normoxic conditions. Thus, we aimed to investigate the mechanism involved in this accumulation. We
found that 15d-PGJ2 induced an over-accumulation of HIF-1α in RCC4 cells, which lack pVHL and in HK-2 cells treated with inhibitors of the pVHL-proteasome
pathway. These results indicated that pVHL-proteasome-independent mechanisms are involved, and therefore we aimed to ascertain
them. We have identified a new lysosomal-dependent mechanism of HIF-1α degradation as a target for 15d-PGJ2 based on: (1) HIF-1α colocalized with the specific lysosomal marker Lamp-2a, (2) 15d-PGJ2 inhibited the activity of cathepsin B, a lysosomal protease, and (3) inhibition of lysosomal activity did not result in over-accumulation
of HIF-1α in 15d-PGJ2-treated cells. Therefore, expression of HIF-1α is also modulated by lysosomal degradation. 相似文献
18.
Eleonora Dondossola Anna Gasparri Angela Bachi Renato Longhi Marie-Hélène Metz-Boutigue Bruno Tota Karen B. Helle Flavio Curnis Angelo Corti 《Cellular and molecular life sciences : CMLS》2010,67(12):2107-2118
Fibroblast adhesion can be modulated by proteins released by neuroendocrine cells and neurons, such as chromogranin A (CgA)
and its N-terminal fragment vasostatin-1 (VS-1, CgA1–78). We have investigated the mechanisms of the interaction of VS-1 with fibroblasts and of its pro-adhesive activity and have
found that the proadhesive activity of VS-1 relies on its interaction with the fibroblast membrane via a phospholipid-binding
amphipathic α-helix located within residues 47–66, as well as on the interaction of the adjacent C-terminal region 67–78,
which is structurally similar to ezrin–radixin–moesin-binding phosphoprotein 50 (a membrane-cytoskeleton adapter protein),
with other cellular components critical for the regulation of cell cytoskeleton. 相似文献
19.
Courtois G 《Cellular and molecular life sciences : CMLS》2008,65(7-8):1123-1132
CYLD is a protein with tumor suppressor properties which was originally discovered associated with cylindromatosis, an inherited
cancer exclusively affecting the folicullo-sebaceous-apocrine unit of the epidermis. CYLD exhibits deubiquitinating activity
and acts as a negative regulator of NF-κB and JNK signaling through its interaction with NEMO and TRAF2. Recent data suggest
that this is unlikely to be its unique function in vivo. CYLD has also been shown to control other seemingly disparate cellular processes, such as proximal T cell receptor signaling,
TrkA endocytosis and mitosis. In each case, this enzyme appears to act by regulating a specific type of polyubiquitination,
K63 polyubiquitination, that does not result in recognition and degradation of proteins by the proteasome but instead controls
their activity through diverse mechanisms.
Received 6 October 2007; received after revision 2 November 2007; accepted 23 November 2007 相似文献
20.
Véronique Pons Nizar Serhan Stéphanie Gayral Camille Malaval Michel Nauze Nicole Malet Muriel Laffargue Céline Galés Laurent O. Martinez 《Cellular and molecular life sciences : CMLS》2014,71(9):1775-1788
The protective effect of high density lipoproteins (HDL) against atherosclerosis is mainly attributed to their capacity to transport excess cholesterol from peripheral tissues back to the liver for further elimination into the bile, a process called reverse cholesterol transport (RCT). Recently, the importance of the P2Y13 receptor (P2Y13-R) was highlighted in HDL metabolism since HDL uptake by the liver was decreased in P2Y13-R deficient mice, which translated into impaired RCT. Here, we investigated for the first time the molecular mechanisms regulating cell surface expression of P2Y13-R. When transiently expressed, P2Y13-R was mainly detected in the endoplasmic reticulum (ER) and strongly subjected to proteasome degradation while its homologous P2Y12 receptor (P2Y12-R) was efficiently targeted to the plasma membrane. We observed an inverse correlation between cell surface expression and ubiquitination level of P2Y13-R in the ER, suggesting a close link between ubiquitination of P2Y13-R and its efficient targeting to the plasma membrane. The C-terminus tail exchange between P2Y13-R and P2Y12-R strongly restored plasma membrane expression of P2Y13-R, suggesting the involvement of the intra-cytoplasmic tail of P2Y13-R in expression defect. Accordingly, proteasomal inhibition increased plasma membrane expression of functionally active P2Y13-R in hepatocytes, and consequently stimulated P2Y13-R-mediated HDL endocytosis. Importantly, proteasomal inhibition strongly potentiated HDL hepatic uptake (>200 %) in wild-type but not in P2Y13-R-deficient mice, thus reinforcing the role of P2Y13-R expression in regulating HDL metabolism. Therefore, specific inhibition of the ubiquitin–proteasome system might be a novel powerful HDL therapy to enhance P2Y13-R expression and consequently promote the overall RCT. 相似文献