ArticleThe Journal of biological chemistry2015
Altered activation of protein kinase PKR and enhanced apoptosis in dystonia cells carrying a mutation in PKR activator protein PACT.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
What it found
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Who cites it
33 citing papers in PubMed, 60 citations in OpenAlex.
- Article
- Essential role of protein kinase R in the pathogenesis of pulmonary veno-occlusive disease.JCI insight · 2025Article
- Cooperative role of PACT and ADAR1 in preventing aberrant PKR activation by self-derived double-stranded RNA.Nature communications · 2025Article
- Emerging Molecular-Genetic Families in Dystonia: Endosome-Autophagosome-Lysosome and Integrated Stress Response Pathways.Movement disorders : official journal of the Movement Disorder Society · 2025Review
- Mutation in Prkra results in cerebellar abnormality and reduced eIF2α phosphorylation in a model of DYT-PRKRA.Disease models & mechanisms · 2024Article
- The integrated stress response in brain diseases: A double-edged sword for proteostasis and synapses.Current opinion in neurobiology · 2024Review
- A frameshift mutation in the murinebioRxiv : the preprint server for biology · 2024Article
- The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia.The Journal of clinical investigation · 2024Review
- The Sixth Sense: Self-nucleic acid sensing in the brain.Advances in immunology · 2024Review
- Genome-wide SNP analysis provides insights into the XX/XY sex-determination system in silver barb (Barbonymus gonionotus).Genomics & informatics · 2023Article
- Luteolin protects DYT-Frontiers in pharmacology · 2023Article
- DYT-Frontiers in neuroscience · 2023Review
- DYT-Biomolecules · 2022Article
- Uniparental disomy screen of Irish rare disorder cohort unmasks homozygous variants of clinical significance in theFrontiers in genetics · 2022Article
- A tale of two proteins: PACT and PKR and their roles in inflammation.The FEBS journal · 2021Review
- The HIV protease inhibitor, ritonavir, corrects diverse brain phenotypes across development in mouse model of DYT-TOR1A dystonia.Science translational medicine · 2021Article
- Regulation of PKR activation and apoptosis during oxidative stress by TRBP phosphorylation.The international journal of biochemistry & cell biology · 2021Article
- Emerging and converging molecular mechanisms in dystonia.Journal of neural transmission (Vienna, Austria : 1996) · 2021Review
- Combined dystonias: clinical and genetic updates.Journal of neural transmission (Vienna, Austria : 1996) · 2021Review
- EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia.Annals of neurology · 2021Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
PACT is a stress-modulated activator of the interferon-induced double-stranded RNA-activated protein kinase (PKR). Stress-induced phosphorylation of PACT is essential for PACT's association with PKR leading to PKR activation. PKR activation leads to phosphorylation of translation initiation factor eIF2α inhibition of protein synthesis and apoptosis. A recessively inherited form of early-onset dystonia DYT16 has been recently identified to arise due to a homozygous missense mutation P222L in PACT. To examine if the mutant P222L protein alters the stress-response pathway, we examined the ability of mutant P222L to interact with and activate PKR. Our results indicate that the substitution mutant P222L activates PKR more robustly and for longer duration albeit with slower kinetics in response to the endoplasmic reticulum stress. In addition, the affinity of PACT-PACT and PACT-PKR interactions is enhanced in dystonia patient lymphoblasts, thereby leading to intensified PKR activation and enhanced cellular death. P222L mutation also changes the affinity of PACT-TRBP interaction after cellular stress, thereby offering a mechanism for the delayed PKR activation in response to stress. Our results demonstrate the impact of a dystonia-causing substitution mutation on stress-induced cellular apoptosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.