Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.27.5 (RNase)
17,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sequence of RNase L has been re-examined by computer analysis. We propose a molecular architecture of RNase L, with an unusual combination, in one protein chain, of 9 ankyrin-like repeats, a functional active protein kinase and a C-terminal catalytic RNase similar to the yeast protein, IRE1. The protein kinase may be involved in a new signal transduction pathway which remains to be discovered.
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PMID:A hybrid protein kinase-RNase in an interferon-induced pathway? 769 13

The 2',5'-oligoadenylate-activated enzyme, RNase L, is an endoribonuclease implicated in the antiviral and apoptotic activities of interferons. To probe the genetics of the 2-5A system, the human and mouse genes were cloned, characterized, and compared. The first coding exon of both genes encodes the regulatory regions of RNase L, 67-70% of the proteins including nine ankyrin repeats, the 2-5A binding domain, and several protein kinase homology motifs. In contrast, the coding sequence for the ribonuclease domain in the mouse and human gene is divided among three exons. The transcriptional start site of the human RNase L gene was located in noncoding exon I by primer extension analysis. A complete coding sequence of mouse RNase L was obtained revealing a 735-amino acid protein with 64% identity to human RNase L. A hypothesis is presented concerning the evolutionary relationship of RNase L to both an ankyrin repeat protein kinase and the kinase-endoribonuclease. IRE1, that mediates the unfolded protein response.
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PMID:Analysis and origins of the human and mouse RNase L genes: mediators of interferon action. 1106 55

Severe hyperhomocysteinemia is associated with endothelial cell injury that may contribute to an increased incidence of thromboembolic disease. In this study, homocysteine induced programmed cell death in human umbilical vein endothelial cells as measured by TdT-mediated dUTP nick end labeling assay, DNA ladder formation, induction of caspase 3-like activity, and cleavage of procaspase 3. Homocysteine-induced cell death was specific to homocysteine, was not mediated by oxidative stress, and was mimicked by inducers of the unfolded protein response (UPR), a signal transduction pathway activated by the accumulation of unfolded proteins in the lumen of the endoplasmic reticulum. Dominant negative forms of the endoplasmic reticulum-resident protein kinases IRE1alpha and -beta, which function as signal transducers of the UPR, prevented the activation of glucose-regulated protein 78/immunoglobulin chain-binding protein and C/EBP homologous protein/growth arrest and DNA damage-inducible protein 153 in response to homocysteine. Furthermore, overexpression of the point mutants of IRE1 with defective RNase more effectively suppressed the cell death than the kinase-defective mutant. These results indicate that homocysteine induces apoptosis in human umbilical vein endothelial cells by activation of the UPR and is signaled through IRE1. The studies implicate that the UPR may cause endothelial cell injury associated with severe hyperhomocysteinemia.
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PMID:Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. 1144 14

Protein transport from the endoplasmic reticulum (ER) to the Golgi apparatus is mediated by transport vesicles coated with the coat protein complex II (COPII). In the process of searching for novel factors that participate in the formation of COPII-coated vesicles (COPII vesicles), we isolated high-copy suppressors of a sec24-20 mutant defective in COPII vesicle formation from the ER at the restrictive temperature. Unexpectedly, one of them was identified as HAC1, a gene encoding the basic leucine-zipper type transcription factor Hac1p. Hac1p is essential for a signaling cascade activated by ER stress, termed the unfolded protein response (UPR) pathway, that leads from the ER to the nucleus. Overexpression of another UPR-related gene IRE1, which encodes an ER-resident transmembrane protein kinase/ribonuclease, also suppressed the growth defect of the sec24-20 mutant in a HAC1-dependent manner. Moreover, overexpression of IRE1 specifically suppressed growth defects of other sec mutants defective in COPII vesicle formation. These findings suggest that the activation of the UPR affects ER-to-Golgi transport via stimulation of COPII vesicle formation from the ER.
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PMID:A genetic link between the unfolded protein response and vesicle formation from the endoplasmic reticulum. 1217 18

Conditions that perturb the function of the endoplasmic reticulum (ER) lead to an accumulation of proteins and subsequent induction of several responses, such as an increased expression of ER-resident chaperones involved in protein folding and activation of c-jun N-terminal kinase (JNK). These responses are mediated by a transmembrane kinase/ribonuclease, IRE1, which transduces the signal from the ER lumen to the cytosol. Although nuclear transcription factor-kappaB (NF-kappaB) is also activated by ER stress, whether this response depends on IRE1 is unknown. In this study, we show that IRE1 is involved in the activation of NF-kappaB induced by ER stress. NF-kappaB was activated by ER stress-inducing agents, thapsigargin and tunicamycin. The activation was inhibited by a dominant-negative IRE1. In addition, a dominant-negative TRAF2 also suppressed the activation of NF-kappaB by ER stress. These results suggest that ER stress-induced NF-kappaB activation is also mediated by the IRE1-TRAF2 pathway, as well as JNK activation.
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PMID:Activation signal of nuclear factor-kappa B in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2. 1284 13

IRE1, an ER-localized transmembrane-RNase, plays a central role in ER stress response. Upon ER stress, IRE1 induces various adaptive genes through the processing of mRNA encoding the transcription factor XBP1. Moreover, it was recently reported that in fly IRE1 attenuates the expression of several genes by cleaving mRNAs, but it has been unclear whether such a mechanism also exists in mammal. In this study, we searched for IRE1alpha-cleaved mRNAs in mammalian cells and identified human CD59 (complement defense 59) mRNA as a novel cleavage target. In addition, the expression of CD59 was significantly attenuated by overexpression of IRE1alpha or ER stress. These results suggest that IRE1alpha-mediated mRNA cleavage functions even in mammals as a common system to regulate gene expression.
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PMID:Site-specific cleavage of CD59 mRNA by endoplasmic reticulum-localized ribonuclease, IRE1. 1758 77

Unfolded proteins in the endoplasmic reticulum (ER) cause trans-autophosphorylation of the bifunctional transmembrane kinase IRE1alpha, inducing its RNase activity to splice XBP1 mRNA, in turn triggering a transcriptional program in the unfolded protein response (UPR). As we previously showed with the yeast IRE1 kinase ortholog, a single missense mutation in the ATP-binding pocket of murine IRE1alpha kinase sensitizes it to the ATP-competitive inhibitor 1NM-PP1, and subordinates RNase activity to the drug. This highly unusual mechanism of kinase signaling requiring kinase domain ligand occupancy-even through an inhibitor-to activate a nearby RNase has therefore been completely conserved through evolution. We also demonstrate that engagement of the drug-sensitized IRE1alpha kinase through this maneuver affords murine cells cytoprotection under ER stress. Thus kinase inhibitors of IRE1alpha are useful for altering the apoptotic outcome to ER stress, and could possibly be developed into drugs to treat ER stress-related diseases.
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PMID:A kinase inhibitor activates the IRE1alpha RNase to confer cytoprotection against ER stress. 1803 51

IRE1 is an atypical serine/threonine kinase transmembrane protein with RNase activity. In the unfolded protein response (UPR), they function as proximal sensor of the unfolded proteins in the endoplasmic reticulum (ER). Upon activation by ER stress, IRE1 performs an unconventional cytoplasmic splicing of XBP1 pre-mRNA and thus allows the synthesis of active XBP1, which activates UPR target genes to restore the homeostasis of the ER. IRE1/XBP1 signaling is hence essential for UPR but its function during embryogenesis is yet unknown. The transcripts of the two isoforms of IRE1 in Xenopus, xIRE1alpha and xIRE1beta are differentially expressed during embryogenesis. We found that xIRE1beta is sufficient for cytoplasmic splicing of xXBP1 pre-mRNA. Although gain of xIRE1beta function had no significant effect on Xenopus embryogenesis, overexpression of both, xIRE1beta and xXBP1 pre-mRNA, inhibits activin A induced mesoderm formation, suggesting that an enhanced activity of the IRE1/XBP1 pathway represses mesoderm formation. Surprisingly, while loss of XBP1 function promotes mesoderm formation, the loss of IRE1beta function led to a reduction of mesoderm formation, probably by action of IRE1 being different from the IRE1/XBP1 pathway. Therefore, both gain and loss of function studies demonstrate that IRE1 is required for mesoderm formation in Xenopus embryos.
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PMID:IRE1beta is required for mesoderm formation in Xenopus embryos. 1819 52

Endoplasmic reticulum (ER) stress is associated with the functional disorder of the ER. During conditions of ER stress, cells induce at least two responses to maintain ER function: transcriptional upregulation of ER quality control genes, and translational attenuation of protein synthesis. Induction of ER quality control proteins is mediated by IRE1alpha, which activates the transcription factor XBP1 via an unconventional splicing event, while a partial translational attenuation is mediated by IRE1beta. Here, we show by both in vivo and in vitro analyses that the RNase domain of IRE1 determines the functional specificities of each of these isoforms.
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PMID:RNase domains determine the functional difference between IRE1alpha and IRE1beta. 1824 82

Assay technologies that were originally developed for high-throughput screening (HTS) have recently proven useful in drug discovery for activities located upstream (target identification and validation) and downstream (ADMET) of HTS. Here the authors investigated and characterized the biological properties of a novel target, IRE1alpha, a bifunctional kinase/RNase stress sensor of the endoplasmic reticulum (ER). They have developed a novel assay platform using the HTS technology AlphaScreen to monitor the dimerization/oligomerization and phosphorylation properties of the cytosolic domain of IRE1alpha. They show in vitro that dimerization/oligomerization of the cytosolic domain of IRE1 correlated with the autophosphorylation ability of this domain and its endoribonuclease activity toward XBP1 mRNA. Using orthogonal in vitro and cell-based approaches, the authors show that the results obtained using AlphaScreen were biologically relevant. Preliminary characterization of assay robustness indicates that both AlphaScreen assays should be useful in HTS for the identification of IRE1 activity modulators.
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PMID:AlphaScreen-based characterization of the bifunctional kinase/RNase IRE1alpha: a novel and atypical drug target. 2023 4


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