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EIF2S1 (phospho S51) antibody [E90]

RRID:AB_732117

Antibody ID

AB_732117

Target Antigen

EIF2S1 (phospho S51) antibody [E90] drosophila/arthropod, mouse, human, non-human primate, rat, yeast/fungi, human, mouse, rat, african green monkey, fruit fly (drosophila melanogaster), neurospora crassa

Proper Citation

(Abcam Cat# ab32157, RRID:AB_732117)

Clonality

monoclonal antibody

Comments

validation status unknown, seller recommendations provided in 2012: Dot, ICC, ICC/IF, IHC-Fr, IHC-P, WB; Dot Blot; Immunofluorescence; Immunohistochemistry; Western Blot; Immunohistochemistry - frozen; Immunocytochemistry; Immunohistochemistry - fixed

Host Organism

rabbit

Vendor

Abcam

The TIA1 RNA-Binding Protein Family Regulates EIF2AK2-Mediated Stress Response and Cell Cycle Progression.

  • Meyer C
  • Mol. Cell
  • 2018 Feb 15

Literature context:


Abstract:

TIA1 and TIAL1 encode a family of U-rich element mRNA-binding proteins ubiquitously expressed and conserved in metazoans. Using PAR-CLIP, we determined that both proteins bind target sites with identical specificity in 3' UTRs and introns proximal to 5' as well as 3' splice sites. Double knockout (DKO) of TIA1 and TIAL1 increased target mRNA abundance proportional to the number of binding sites and also caused accumulation of aberrantly spliced mRNAs, most of which are subject to nonsense-mediated decay. Loss of PRKRA by mis-splicing triggered the activation of the double-stranded RNA (dsRNA)-activated protein kinase EIF2AK2/PKR and stress granule formation. Ectopic expression of PRKRA cDNA or knockout of EIF2AK2 in DKO cells rescued this phenotype. Perturbation of maturation and/or stability of additional targets further compromised cell cycle progression. Our study reveals the essential contributions of the TIA1 protein family to the fidelity of mRNA maturation, translation, and RNA-stress-sensing pathways in human cells.

Funding information:
  • Howard Hughes Medical Institute - R01 GM104962()
  • NIDDK NIH HHS - R01 DK068429(United States)

Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown.

  • Chung H
  • Cell
  • 2018 Feb 8

Literature context:


Abstract:

Type I interferon (IFN) is produced when host sensors detect foreign nucleic acids, but how sensors differentiate self from nonself nucleic acids, such as double-stranded RNA (dsRNA), is incompletely understood. Mutations in ADAR1, an adenosine-to-inosine editing enzyme of dsRNA, cause Aicardi-Goutières syndrome, an autoinflammatory disorder associated with spontaneous interferon production and neurologic sequelae. We generated ADAR1 knockout human cells to explore ADAR1 substrates and function. ADAR1 primarily edited Alu elements in RNA polymerase II (pol II)-transcribed mRNAs, but not putative pol III-transcribed Alus. During the IFN response, ADAR1 blocked translational shutdown by inhibiting hyperactivation of PKR, a dsRNA sensor. ADAR1 dsRNA binding and catalytic activities were required to fully prevent endogenous RNA from activating PKR. Remarkably, ADAR1 knockout neuronal progenitor cells exhibited MDA5 (dsRNA sensor)-dependent spontaneous interferon production, PKR activation, and cell death. Thus, human ADAR1 regulates sensing of self versus nonself RNA, allowing pathogen detection while avoiding autoinflammation.

Funding information:
  • NCRR NIH HHS - M01-RR00425(United States)
  • NIAID NIH HHS - F32 AI114211()
  • NIAID NIH HHS - R01 AI091707()

CpG and UpA dinucleotides in both coding and non-coding regions of echovirus 7 inhibit replication initiation post-entry.

  • Fros JJ
  • Elife
  • 2017 Sep 29

Literature context:


Abstract:

Most vertebrate and plant RNA and small DNA viruses suppress genomic CpG and UpA dinucleotide frequencies, apparently mimicking host mRNA composition. Artificially increasing CpG/UpA dinucleotides attenuates viruses through an entirely unknown mechanism. Using the echovirus 7 (E7) model in several cell types, we show that the restriction in E7 replication in mutants with increased CpG/UpA dinucleotides occurred immediately after viral entry, with incoming virions failing to form replication complexes. Sequences of CpG/UpA-high virus stocks showed no evidence of increased mutational errors that would render them replication defective, these viral RNAs were not differentially sequestered in cytoplasmic stress granules nor did they induce a systemic antiviral state. Importantly, restriction was not mediated through effects on translation efficiency since replicons with high CpG/UpA sequences inserted into a non-coding region were similarly replication defective. Host-cells thus possess intrinsic defence pathways that prevent replication of viruses with increased CpG/UpA frequencies independently of codon usage.

The integrated stress response in hypoxia-induced diffuse white matter injury.

  • Clayton BL
  • J. Neurosci.
  • 2017 Jul 18

Literature context:


Abstract:

Currently no treatments exist for preterm infants with diffuse white matter injury (DWMI) caused by hypoxia. Due to improved care of preterm neonates and increased recognition by advanced imaging techniques, the prevalence of DWMI is increasing. A better understanding of the pathophysiology of DWMI is therefore of critical importance. The integrated stress response (ISR), a conserved eukaryotic response to myriad stressors including hypoxia, may play a role in hypoxia-induced DWMI and may represent a novel target for much needed therapies. In this study we utilize in vitro and in vivo hypoxic models of DWMI to investigate whether the ISR is involved in DWMI. We demonstrate that hypoxia activates the ISR in primary mouse oligodendrocyte precursor cells (OPCs) in vitro and that genetically inhibiting the ISR in differentiating OPCs increases their susceptibility to in vitro hypoxia. We also show that a well-established in vivo mild chronic hypoxia (MCH) mouse model and a new severe acute hypoxia (SAH) mouse model of DWMI activates the initial step of the ISR. Nonetheless, genetic inhibition of the ISR has no detectable effect on either MCH or SAH-induced DWMI. In addition, we demonstrate that genetic enhancement of the ISR does not ameliorate MCH or SAH-induced DWMI. These studies suggest that while the ISR protects OPCs from hypoxia in vitro, it does not appear to play a major role in either MCH or SAH-induced DWMI and is therefore not a likely target for therapies aimed at improving neurological outcome in preterm neonates with hypoxia-induced DWMI.SIGNIFICANCE STATEMENTDiffuse white matter injury (DWMI) caused by hypoxia is a leading cause of neurological deficits following premature birth. An increased understanding of the pathogenesis of this disease is critical. The integrated stress response (ISR) is activated by hypoxia and protects oligodendrocyte lineage cells in other disease models. This has led to an interest in the potential role of the ISR in DWMI. Here we examine the ISR in hypoxia-induced DWMI and show that while the ISR protects oligodendrocyte lineage cells from hypoxia in vitro, genetic inhibition or enhancement of the ISR has no effect on hypoxia-induced DWMI in vivo suggesting that the ISR does not play a major role in, and is not a likely therapeutic target for, DWMI.

Funding information:
  • NINDS NIH HHS - R01 NS034939()

Neuroprotection and Blood-Brain Barrier Restoration by Salubrinal After a Cortical Stab Injury.

  • Barreda-Manso MA
  • J. Cell. Physiol.
  • 2017 Jun 18

Literature context:


Abstract:

Following a central nervous system (CNS) injury, restoration of the blood-brain barrier (BBB) integrity is essential for recovering homeostasis. When this process is delayed or impeded, blood substances and cells enter the CNS parenchyma, initiating an additional inflammatory process that extends the initial injury and causes so-called secondary neuronal loss. Astrocytes and profibrotic mesenchymal cells react to the injury and migrate to the lesion site, creating a new glia limitans that restores the BBB. This process is beneficial for the resolution of the inflammation, neuronal survival, and the initiation of the healing process. Salubrinal is a small molecule with neuroprotective properties in different animal models of stroke and trauma to the CNS. Here, we show that salubrinal increased neuronal survival in the neighbourhood of a cerebral cortex stab injury. Moreover, salubrinal reduced cortical blood leakage into the parenchyma of injured animals compared with injured controls. Adjacent to the site of injury, salubrinal induced immunoreactivity for platelet-derived growth factor subunit B (PDGF-B), a specific mitogenic factor for mesenchymal cells. This effect might be responsible for the increased immunoreactivity for fibronectin and the decreased activation of microglia and macrophages in injured mice treated with salubrinal, compared with injured controls. The immunoreactivity for PDGF-B colocalized with neuronal nuclei (NeuN), suggesting that cortical neurons in the proximity of the injury were the main source of PDGF-B. Our results suggest that after an injury, neurons play an important role in both, the healing process and the restoration of the BBB integrity. J. Cell. Physiol. 232: 1501-1510, 2017. © 2016 Wiley Periodicals, Inc.

Funding information:
  • Wellcome Trust - 102645(United Kingdom)

PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz.

  • Crespillo-Casado A
  • Elife
  • 2017 Apr 27

Literature context:


Abstract:

Dephosphorylation of translation initiation factor 2 (eIF2α) terminates signalling in the mammalian integrated stress response (ISR) and has emerged as a promising target for modifying the course of protein misfolding diseases. The [(o-chlorobenzylidene)amino]guanidines (Guanabenz and Sephin1) have been proposed to exert protective effects against misfolding by interfering with eIF2α-P dephosphorylation through selective disruption of a PP1-PPP1R15A holophosphatase complex. Surprisingly, they proved inert in vitro affecting neither stability of the PP1-PPP1R15A complex nor substrate-specific dephosphorylation. Furthermore, eIF2α-P dephosphorylation, assessed by a kinase shut-off experiment, progressed normally in Sephin1-treated cells. Consistent with its role in defending proteostasis, Sephin1 attenuated the IRE1 branch of the endoplasmic reticulum unfolded protein response. However, repression was noted in both wildtype and Ppp1r15a deleted cells and in cells rendered ISR-deficient by CRISPR editing of the Eif2s1 locus to encode a non-phosphorylatable eIF2α (eIF2αS51A). These findings challenge the view that [(o-chlorobenzylidene)amino]guanidines restore proteostasis by interfering with eIF2α-P dephosphorylation.