A5025998272- Endoplasmic Reticulum Stress and Disease
- RNA regulation and disease
- RNA Research and Splicing
- CRISPR and Genetic Engineering
- RNA and protein synthesis mechanisms
- Toxoplasma gondii Research Studies
- Heat shock proteins research
- Biochemical and Molecular Research
- Toxin Mechanisms and Immunotoxins
- Pancreatic function and diabetes
- interferon and immune responses
- Cytomegalovirus and herpesvirus research
- Genomics and Phylogenetic Studies
- Lipid Membrane Structure and Behavior
- DNA Repair Mechanisms
- Moyamoya disease diagnosis and treatment
- Transgenic Plants and Applications
- Cancer Research and Treatments
- Hereditary Neurological Disorders
- Ubiquitin and proteasome pathways
- Adenosine and Purinergic Signaling
MRC Laboratory of Molecular Biology
2021-2024
University of Cambridge
2014-2020
NIHR Cambridge Biomedical Research Centre
2015
Wellcome/MRC Institute of Metabolic Science
2015
Wellcome Trust
2015
The integrated stress response (ISR) modulates messenger RNA translation to regulate the mammalian unfolded protein (UPR), immunity, and memory formation. A chemical ISR inhibitor, ISRIB, enhances cognitive function UPR in vivo. To explore mechanisms involved ISRIB action, we screened cultured cells for somatic mutations that reversed its effect on ISR. Clustered missense were found at amino-terminal portion of delta subunit guanine nucleotide exchange factor (GEF) eIF2B. When reintroduced...
ISRIB mechanism of action In rodents, a druglike small molecule named enhances cognition and reverses cognitive deficits after traumatic brain injury. activates protein complex called eIF2B that is required for the synthesis new proteins. Tsai et al. report visualization bound to at near-atomic resolution by cryo–electron microscopy. Biochemical studies revealed “molecular staple” promotes assembly fully active form eIF2B. Zyryanova similar structures together with information on binding...
The small molecule ISRIB antagonizes the activation of integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange for eIF2. We have found that ISRIB-mediated acceleration eIF2B's activity vitro is observed preferentially presence attenuated mutations desensitize eIF2B to inhibitory effect ISRIB's efficacy as an ISR inhibitor cells also depends on Cryoelectron...
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 course protein misfolding diseases. The [(o-chlorobenzylidene)amino]guanidines (Guanabenz Sephin1) have been proposed to exert protective effects against by interfering with eIF2α-P dephosphorylation through selective disruption PP1-PPP1R15A holophosphatase complex. Surprisingly, they proved inert vitro...
Dephosphorylation of eukaryotic translation initiation factor 2a (eIF2a) restores protein synthesis at the waning stress responses and requires a PP1 catalytic subunit regulatory subunit, PPP1R15A/GADD34 or PPP1R15B/CReP. Surprisingly, PPP1R15-PP1 binary complexes reconstituted in vitro lacked substrate selectivity. However, selectivity was restored by crude cell lysate purified G-actin, which joined to form stable ternary complex. In crystal structures non-selective PPP1R15B-PP1G complex,...
DnaK/Hsp70 chaperones form oligomers of poorly understood structure and functional significance. Site-specific proteolysis crosslinking were used to probe the architecture formed by endoplasmic reticulum (ER) Hsp70, BiP. These found consist adjacent protomers engaging interdomain linker one molecule in substrate binding site another, attenuating chaperone function oligomeric Native gel electrophoresis revealed a rapidly-modulated reciprocal relationship between burden unfolded proteins BiP...
Endoplasmic reticulum (ER) lumenal protein thiol redox balance resists dramatic variation in unfolded load imposed by diverse physiological challenges including compromise the key upstream oxidases. Lumenal calcium depletion, incurred during normal cell signaling, stands out as a notable exception to this resilience, promoting rapid and reversible shift towards more reducing poise. Calcium depletion induced ER alterations are relevant conditions associated with such response of pancreatic...
The integrated stress response (ISR) is regulated by kinases that phosphorylate the α subunit of translation initiation factor 2 and phosphatases dephosphorylate it. Genetic biochemical observations indicate eIF2αP-directed holophosphatase, a therapeutic target in diseases protein misfolding, comprised regulatory subunit, PPP1R15, catalytic phosphatase 1 (PP1). In mammals, there are two isoforms PPP1R15A PPP1R15B, with overlapping roles essential function eIF2αP dephosphorylation. However,...
The eukaryotic translation initiation factor eIF2B promotes mRNA as a guanine nucleotide exchange (GEF) for 2 (eIF2). Endoplasmic reticulum (ER) stress-mediated activation of the kinase PERK and resultant phosphorylation eIF2's alpha subunit (eIF2α) attenuates GEF activity thereby inducing an integrated stress response (ISR) that defends against protein misfolding in ER. Mutations all five subunits human cause inherited leukoencephalopathy with vanishing white matter (VWM), but role ISR its...
The evolutionary arms race between pathogens and hosts has resulted in acquiring diverse adaptive countermeasures that antagonize host immunity. Ubiquitylation of lipopolysaccharide (LPS) on cytosol-invading bacteria by the E3 ligase RNF213 creates 'eat-me' signals for antibacterial autophagy but whether how cytosol-adapted avoid LPS ubiquitylation remains poorly understood. Here we show Shigella flexneri, a professional cytosol-dwelling enterobacterium, actively antagonizes through IpaH1.4,...
The aminoguanidine compound robenidine is widely used as an antibiotic for the control of coccidiosis, a protozoal infection in poultry and rabbits. Interestingly, structurally similar to guanabenz (analogs), which are currently undergoing clinical trials cytoprotective agents management neurodegenerative diseases. Here we show that protect cells from tunicamycin-induced unfolded protein response degree. Both compounds also reduced tumor necrosis factor α-induced activation NF-κB. effects...
Innate immunity senses microbial ligands known as pathogen-associated molecular patterns (PAMPs). Except for nucleic acids, PAMPs are exceedingly taxa-specific, thus enabling pattern recognition receptors to detect cognate pathogens while ignoring others. How the E3 ubiquitin ligase RNF213 can respond phylogenetically distant pathogens, including Gram-negative Salmonella, Gram-positive Listeria, and eukaryotic Toxoplasma, remains unknown. Here we report that evolutionary history of is...
Abstract The small molecule ISRIB antagonises the activation of integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange (GEF) for eIF2. We have found that ISRIB-mediated acceleration eIF2B activity vitro is observed preferentially presence attenuated mutations desensitise to inhibitory effects ISRIB’s efficacy as an ISR inhibitor cells also depends on Cryo-EM...
Abstract The Integrated Stress Response (ISR) is a conserved eukaryotic translational and transcriptional program implicated in mammalian metabolism, memory immunity. ISR mediated by stress-induced phosphorylation of translation initiation factor 2 (eIF2) that attenuates the guanine nucleotide exchange eIF2B. A chemical inhibitor ISR, ISRIB, bis-O-arylglycolamide, reverses attenuation eIF2B phosphorylated eIF2, protecting mice from neurodegeneration traumatic brain injury. We report on...
ABSTRACT The integrated stress response (ISR) is regulated by kinases that phosphorylate the α subunit of translation initiation factor 2 and phosphatases dephosphorylate it. Genetic biochemical observations indicate eIF2α P -directed holophosphatase - a therapeutic target in diseases protein misfolding comprised regulatory, PPP1R15, catalytic, Protein Phosphatase 1 (PP1) subunit. In mammals, there are two isoforms regulatory subunit, PPP1R15A PPP1R15B, with overlapping roles promoting...