165 results found
    1. Biochemistry and Chemical Biology
    2. Cell Biology

    Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response

    Carmela Sidrauski et al.
    A drug-like molecule called ISRIB, which activates the translation initiation factor eIF2B, antagonizes stress responses as diverse as protein misfolding and nutrient deprivation, and restores protein synthesis, enhancing memory.
    1. Biochemistry and Chemical Biology
    2. Chromosomes and Gene Expression

    Fail-safe control of translation initiation by dissociation of eIF2α phosphorylated ternary complexes

    Martin D Jennings et al.
    Phosphorylated translation initiation factor eIF2, a potent inhibitor of protein synthesis in eukaryotic cells, is also inhibitory to protein synthesis when bound to GTP and initiator tRNA broadening the reach and immediacy of eIF2-mediated control.
    1. Medicine

    Vanishing white matter disease expression of truncated EIF2B5 activates induced stress response

    Matthew D Keefe et al.
    Neurological pathology and chronic activation of the induced stress response are caused by expression of a truncated EIF2B5 in vanishing white matter disease.
    1. Biochemistry and Chemical Biology
    2. Cell Biology

    The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes

    Yao Liang Wong et al.
    Vanishing White Matter Disease mutations compromise the function of the essential translation initiation factor eIF2B by destabilizing the holoenzyme, and the small molecule ISRIB reverses their pathogenic effect by promoting complex formation.
    1. Biochemistry and Chemical Biology
    2. Chromosomes and Gene Expression

    Interface between 40S exit channel protein uS7/Rps5 and eIF2α modulates start codon recognition in vivo

    Jyothsna Visweswaraiah, Alan G Hinnebusch
    The small subunit ribosomal protein uS7/Rps5 interacts with translation initiation factor eIF2α to stabilize first the open, and then the closed conformation of the pre-initiation complex to promote accurate start codon selection in vivo.
    1. Biochemistry and Chemical Biology
    2. Cell Biology

    eIF2B conformation and assembly state regulate the integrated stress response

    Michael Schoof et al.
    eIF2-P activates the integrated stress response by inducing a conformational change in eIF2B that decreases substrate (eIF2) binding and reduces eIF2B's catalytic activity.
    1. Neuroscience

    GSK3β regulates AKT-induced central nervous system axon regeneration via an eIF2Bε-dependent, mTORC1-independent pathway

    Xinzheng Guo et al.
    The AKT-GSK3β-eIF2Bε signaling module plays a key role in promoting axon regeneration in the adult mammalian central nervous system.
    1. Biochemistry and Chemical Biology
    2. Neuroscience

    eIF2B activator prevents neurological defects caused by a chronic integrated stress response

    Yao Liang Wong et al.
    Boosting the function of translation factor eIF2B by chronic small molecule administration prevents pathology in a neurodegenerative model of Vanishing White Matter disease characterized by a maladaptive stress response.
    1. Neuroscience

    Translational control of nicotine-evoked synaptic potentiation in mice and neuronal responses in human smokers by eIF2α

    Andon N Placzek et al.
    An evolutionarily conserved mechanism involving translational control by p-eIF2α underlies vulnerability to nicotine addiction.
    1. Cell Biology
    2. Neuroscience

    The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly

    Carmela Sidrauski et al.
    Building on previous work which showed that the small molecule ISRIB potently blocks the integrated stress response (Sidrauski et al., 2013), we report on ISRIB's remarkable specificity and fast action in vivo, underscoring its proposed direct effect on translation.

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