Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Misfolded proteins in the endoplasmic reticulum (ER) are eliminated by a process known as ER-associated degradation (ERAD), which starts with misfolded protein recognition, followed by ubiquitination, retrotranslocation to the cytosol, deglycosylation, and targeting to the proteasome for degradation. Actions of multisubunit protein machineries in the ER membrane integrate these steps. We hypothesized that regulation of the multisubunit machinery assembly is a mechanism by which ERAD activity is regulated. To test this hypothesis, we investigated the potential regulatory role of the small p97/VCP-interacting protein (SVIP) on the formation of the ERAD machinery that includes ubiquitin ligase gp78, AAA ATPase p97/VCP, and the putative channel Derlin1. We found that SVIP is anchored to microsomal membrane via myristoylation and co-fractionated with gp78, Derlin1, p97/VCP, and calnexin to the ER. Like gp78, SVIP also physically interacts with p97/VCP and Derlin1. Overexpression of SVIP blocks unassembled CD3delta from association with gp78 and p97/VCP, which is accompanied by decreases in CD3delta ubiquitination and degradation. Silencing SVIP expression markedly enhances the formation of gp78-p97/VCP-Derlin1 complex, which correlates with increased degradation of CD3delta and misfolded Z variant of alpha-1-antitrypsin, established substrates of gp78. These results suggest that SVIP is an endogenous inhibitor of ERAD that acts through regulating the assembly of the gp78-p97/VCP-Derlin1 complex.
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PMID:Identification of SVIP as an endogenous inhibitor of endoplasmic reticulum-associated degradation. 1787 46

The elimination of misfolded proteins, known as protein quality control, is an essential cellular process. Removal of misfolded proteins from the secretory pathway depends on their recognition in the endoplasmic reticulum (ER) followed by their retrograde transport into the cytosol for degradation. The AAA-ATPase Cdc48/p97 facilitates the translocation of misfolded ER-proteins into the cytosol. Cdc48/p97 can dock onto the ER-membrane via direct interaction with ER-membrane proteins and/or indirectly via its substrate-recruiting cofactors, which interact with the ubiquitylated substrates at the membrane. This tight interaction in conjunction with the conformational changes induced upon ATP hydrolysis within Cdc48/p97 is thought to provide the driving force for the translocation reaction. Subsequently, a series of protein-protein interactions between the Cdc48/p97 complex, its cofactors, and the ubiquitylated substrates is instrumental for the proper delivery of the ER substrates to the proteasome. These protein-protein interactions are governed mainly by ubiquitin-fold and ubiquitin-binding domains.
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PMID:Ubiquitin receptors and ERAD: a network of pathways to the proteasome. 1794 49

The 97 kDa valosin-containing protein (VCP) belongs to a highly conserved AAA (ATPases associated with a variety of activities) family and contains two ATPase domains, D1 and D2. VCP participates in numerous cellular activities, such as membrane fusion, postmitotic Golgi reassembly, endoplasmic reticulum-associated degradation, ubiquitin-proteasome-mediated proteolysis, and many others. In performing these activities, VCP presumably acts as a molecular chaperone that prevents protein aggregation and modifies protein conformation. In this study, we characterized the aggregation-prevention activity of VCP and identified the structural requirement for this activity. We used multiple methods to treat aggregation-prone luciferase (Luc) and showed that VCP prevents the aggregation of Luc in vitro. These results are in agreement; in vivo RNA interference analyses showed that a reduction of VCP level results in more aggregation of Luc in cells. Structural and functional analyses further demonstrated that the D1 domain of VCP is sufficient to mediate the aggregation-prevention activity, which does not require ATP binding, ATP hydrolysis, or a hexameric structure of VCP. Together, these results indicate that (1) VCP prevents protein aggregation in vitro and in vivo, (2) this aggregation-prevention activity is mediated mainly through the D1 domain of VCP, and (3) this activity does not require ATPase activity or a hexameric structure of VCP.
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PMID:Characterization of the aggregation-prevention activity of p97/valosin-containing protein. 1804 63

p97, an essential chaperone in endoplasmic reticulum-associated degradation and organelle biogenesis, contains two AAA domains (D1 and D2) and assembles as a stable hexamer. We present a quantitative analysis of nucleotide binding to both D1 and D2 domains of p97, the first detailed study of nucleotide binding to both AAA domains for this type of AAA+ ATPase. We report that adenosine 5'-O-(thiotriphosphate) (ATPgammaS) binds with similar affinity to D1 and D2, but ADP binds with higher affinity to D1 than D2, offering an explanation for the higher ATPase activity in D2. Stoichiometric measurements suggest that although both ADP and ATPgammaS can saturate all 6 nucleotide binding sites in D1, only 3-4 of the 6 D2 sites can bind ATPgammaS simultaneously. ATPgammaS binding triggers a downstream cooperative conformational change of at least three monomers, which involves conserved arginine fingers and is necessary for ATP hydrolysis.
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PMID:Analysis of nucleotide binding to P97 reveals the properties of a tandem AAA hexameric ATPase. 1833 43

To identify new components of the protein quality control and degradation pathway of the endoplasmic reticulum (ER), we performed a growth-based genome-wide screen of about 5000 viable deletion mutants of the yeast Saccharomyces cerevisiae. As substrates we used two misfolded ER membrane proteins, CTL* and Sec61-2L, chimeric derivatives of the classical ER degradation substrates CPY* and Sec61-2. Both substrates contain a cytosolic Leu2 protein fusion, and stabilization of these substrates in ER-associated degradation-deficient strains enables a restored growth of the transformed LEU2-deficient deletion mutants. We identified the strain deleted for the ubiquitin chain elongating ligase Hul5 among the mutant strains with a strong growth phenotype. Here we show that Hul5 is necessary for the degradation of two misfolded ER membrane substrates. Although the degradation of their N-terminal parts is Hul5-independent, the breakdown of their C-terminal fragments requires the ubiquitin chain elongating ligase activity of Hul5. In the absence of Hul5, a truncated form of CTL*myc remains to a large extent embedded in the ER membrane. Hul5 activity promotes the interaction of this truncated CTL*myc with the AAA-ATPase Cdc48, which is known to pull proteins out of the ER membrane. This study unravels the stepwise elimination of the ER membrane-localized CTL*myc substrate. First, N-terminal, lumenal CPY* is transferred to the cytoplasm and degraded by the proteasome. Subsequently, the remaining C-terminal membrane-anchored part requires Hul5 for its effective extraction out of the endoplasmic reticulum and proteasomal degradation.
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PMID:Ubiquitin ligase Hul5 is required for fragment-specific substrate degradation in endoplasmic reticulum-associated degradation. 1843 32

The ATPase associated with various cellular activities (AAA-ATPase) p97 (p97) has been implicated in the retrotranslocation of target proteins for delivery to the cytosolic proteasome during endoplasmic reticulum-associated degradation (ERAD). Apolipoprotein B-100 (apoB-100) is an ERAD substrate in liver cells, including the human hepatoma, HepG2. We studied the potential role of p97 in the ERAD of apoB-100 in HepG2 cells using cell permeabilization, coimmunoprecipitation, and gene silencing. Degradation was abolished when HepG2 cytosol was removed by digitonin permeabilization, and treatment of intact cells with the proteasome inhibitor MG132 caused accumulation of ubiquitinated apoB protein in the cytosol. Cross-linking of intact cells with the thiol-cleavable agent dithiobis(succinimidylpropionate) (DSP), as well as nondenaturing immunoprecipitation, demonstrated an interaction between p97 and intracellular apoB. Small interfering ribonucleic acid (siRNA)-mediated reduction of p97 protein increased the intracellular levels of newly synthesized apoB-100, predominantly because of a decrease in the turnover of newly synthesized apoB-100 protein. However, although the posttranslational degradation of newly synthesized apoB-100 was delayed by p97 knockdown, secretion of apoB-100 was not affected. Knockdown of p97 also impaired the release of apoB-100 and polyubiquitinated apoB into the cytosol. In summary, our results suggest that retrotranslocation and proteasomal degradation of apoB-100 can be dissociated in HepG2 cells, and that the AAA-ATPase p97 is involved in the removal of full-length apoB from the biosynthetic pathway to the cytosolic proteasome.
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PMID:The AAA-ATPase p97 facilitates degradation of apolipoprotein B by the ubiquitin-proteasome pathway. 1855 Aug 91

p97/VCP (valosin-containing protein) is a cytosolic AAA (ATPase associated with various cellular activities) essential for retrotranslocation of misfolded proteins during ERAD [ER (endoplasmic reticulum)-associated degradation]. gp78, an ERAD ubiquitin ligase, is one of the p97/VCP recruitment proteins localized to the ER membrane. A newly identified VIM (p97/VCP-interacting motif) in gp78 has brought about novel insights into mechanisms of ERAD, such as the presence of a p97/VCP-dependent but Ufd1-independent retrotranslocation during gp78-mediated ERAD. Additionally, SVIP (small p97/VCP-interacting protein), which contains a VIM in its N-terminal region, negatively regulates ERAD by uncoupling p97/VCP and Derlin1 from gp78. Thus SVIP may protect cells from damage by extravagant ERAD.
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PMID:Regulation of ER-associated degradation via p97/VCP-interacting motif. 1879 43

p97/VCP, a member of the AAA-ATPase super family, has been associated with a wide variety of essential cellular protein pathways com prising: (i) nuclear envelope reconstruction, (ii) cell cycle, (iii) Golgi reassembly, (iv) suppression of apoptosis and (v) DNA-damage response [1-6]. In addition, vasolin-containing protein (VCP) dislodges the ubiquitinated proteins from the endoplasmic reticulum (ER) and chaperones them to the cytosol for proteasomal degradation by endoplasmic reticulum-associated degradation (ERAD) [7]. The interactions of VCP in the endoplasmic reticulum-associated degradation (ERAD) pathway determine the substrate selection for proteasomal degradation. Moreover, the interaction with VCP is also required for the ubiquitination of substrate. VCP is phosphorylated by the master cellular kinase, Akt as a mechanism to regulate ERAD [8]. These multiple interactions in protein degradation pathways points to central role of VCP in misfolded protein degradation. VCP has a polyglutamine and ubiquitin-binding capacity and is involved in proteasomal degradation, cytosolic aggregation and processing of polyQ and polyUb aggregates in neurodegenerative and other misfolded protein diseases [9, 10]. Mutations in VCP gene are also linked to a protein deposition disorder, IBMFD [11]. We propose VCP as a therapeutic target for diseases caused by cytosolic protein aggregation or degradation of misfolded protein. We predict that selective interference of VCP interaction(s) with aberrant protein or its ERAD function will be an effective therapeutic site to rescue functional misfolded protein in diseases like cystic fibrosis and alpha-1-trypsin deficiency. The control of VCP expression is also proposed to be a potential therapeutic target in ex-polyQ-induced neurodegenerative diseases [12]. The further functional characterization of VCP and associated proteins in these diseases will help in designing of selective therapeutics.
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PMID:AAA ATPase p97/VCP: cellular functions, disease and therapeutic potential. 1879 39

Salicylic acid (SA) is a critical mediator of plant innate immunity. It plays an important role in limiting the growth and reproduction of the virulent powdery mildew (PM) Golovinomyces orontii on Arabidopsis (Arabidopsis thaliana). To investigate this later phase of the PM interaction and the role played by SA, we performed replicated global expression profiling for wild-type and SA biosynthetic mutant isochorismate synthase1 (ics1) Arabidopsis from 0 to 7 d after infection. We found that ICS1-impacted genes constitute 3.8% of profiled genes, with known molecular markers of Arabidopsis defense ranked very highly by the multivariate empirical Bayes statistic (T(2) statistic). Functional analyses of T(2)-selected genes identified statistically significant PM-impacted processes, including photosynthesis, cell wall modification, and alkaloid metabolism, that are ICS1 independent. ICS1-impacted processes include redox, vacuolar transport/secretion, and signaling. Our data also support a role for ICS1 (SA) in iron and calcium homeostasis and identify components of SA cross talk with other phytohormones. Through our analysis, 39 novel PM-impacted transcriptional regulators were identified. Insertion mutants in one of these regulators, PUX2 (for plant ubiquitin regulatory X domain-containing protein 2), results in significantly reduced reproduction of the PM in a cell death-independent manner. Although little is known about PUX2, PUX1 acts as a negative regulator of Arabidopsis CDC48, an essential AAA-ATPase chaperone that mediates diverse cellular activities, including homotypic fusion of endoplasmic reticulum and Golgi membranes, endoplasmic reticulum-associated protein degradation, cell cycle progression, and apoptosis. Future work will elucidate the functional role of the novel regulator PUX2 in PM resistance.
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PMID:Temporal global expression data reveal known and novel salicylate-impacted processes and regulators mediating powdery mildew growth and reproduction on Arabidopsis. 1917 22

AAA ATPase VCP and its yeast ortholog Cdc48, in a complex with the Ufd1-Npl4 heterodimer as an adaptor, play an essential role in endoplasmic reticulum-associated degradation (ERAD). Several UBX domain-containing proteins function to recruit ubiquitylated substrates to VCP/Cdc48 by binding both VCP/Cdc48 and other ERAD components such as ubiquitin ligases. Here we show that mammalian UBXD1 is an additional UBX domain-containing protein involved in the ERAD process. UBXD1 is a cytosolic protein that interacts with VCP and Derlin-1. Overexpression of UBXD1 in cells causes selective dissociation of Ufd1 from VCP, resulting in inhibition of mutant cystic fibrosis transmembrane conductance regulator (CFTR) degradation by ERAD. Additionally, depletion of endogenous UBXD1 protein by RNA interference also results in a defect in CFTR degradation. Collectively, these findings suggest that UBXD1 is a regulatory component of ERAD that may modulate the adaptor binding to VCP.
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PMID:UBXD1 is a VCP-interacting protein that is involved in ER-associated degradation. 1927 85


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