Dystonia 16 (DYT16) mutations in PACT cause dysregulated PKR activation and eIF2α signaling leading to a compromised stress response
| Autor: | Lauren S. Vaughn, Rekha C. Patel, Nutan Sharma, Samuel B. Burnett, Ronit Kulkarni |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Dystonia 16
0301 basic medicine Prkra viruses Eukaryotic Initiation Factor-2 Mutation Missense Apoptosis Pact DYT16 environment and public health lcsh:RC321-571 eIF-2 Kinase 03 medical and health sciences Transactivation 0302 clinical medicine Humans Integrated stress response ISR PACT Protein kinase A lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Chemistry Endoplasmic reticulum RNA-Binding Proteins virus diseases PKR biochemical phenomena metabolism and nutrition Protein kinase R Cell biology Oxidative Stress enzymes and coenzymes (carbohydrates) 030104 developmental biology Neurology Dystonic Disorders Unfolded protein response Phosphorylation Protein Processing Post-Translational 030217 neurology & neurosurgery Protein Binding Signal Transduction |
| Zdroj: | Neurobiology of Disease, Vol 146, Iss, Pp 105135-(2020) |
| ISSN: | 0969-9961 |
| Popis: | Dystonia 16 (DYT16) is caused by mutations in PACT, the protein activator of interferon-induced double-stranded RNA-activated protein kinase (PKR). PKR regulates the integrated stress response (ISR) via phosphorylation of the translation initiation factor eIF2α. This post-translational modification attenuates general protein synthesis while concomitantly triggering enhanced translation of a few specific transcripts leading either to recovery and homeostasis or cellular apoptosis depending on the intensity and duration of stress signals. PKR plays a regulatory role in determining the cellular response to viral infections, oxidative stress, endoplasmic reticulum (ER) stress, and growth factor deprivation. In the absence of stress, both PACT and PKR are bound by their inhibitor transactivation RNA-binding protein (TRBP) thereby keeping PKR inactive. Under conditions of cellular stress these inhibitory interactions dissociate facilitating PACT-PACT interactions critical for PKR activation. While both PACT-TRBP and PKR-TRBP interactions are pro-survival, PACT-PACT and PACT-PKR interactions are pro-apoptotic. In this study we evaluate if five DYT16 substitution mutations alter PKR activation and ISR. Our results indicate that the mutant DYT16 proteins show stronger PACT-PACT interactions and enhanced PKR activation. In DYT16 patient derived lymphoblasts the enhanced PACT-PKR interactions and heightened PKR activation leads to a dysregulation of ISR and increased apoptosis. More importantly, this enhanced sensitivity to ER stress can be rescued by luteolin, which disrupts PACT-PKR interactions. Our results not only demonstrate the impact of DYT16 mutations on regulation of ISR and DYT16 etiology but indicate that therapeutic interventions could be possible after a further evaluation of such strategies. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect