DYT- PRKRA Mutation P222L Enhances PACT's Stimulatory Activity on Type I Interferon Induction.
Lauren S VaughnKenneth FrederickSamuel B BurnettNutan SharmaD Cristopher BraggSarah CamargosFrancisco CardosoRekha C PatelPublished in: Biomolecules (2022)
DYT- PRKRA (dystonia 16 or DYT- PRKRA ) is caused by mutations in the PRKRA gene that encodes PACT, the protein activator of interferon (IFN)-induced double-stranded (ds) RNA-activated protein kinase (PKR). PACT participates in several cellular pathways, of which its role as a PKR activator protein during integrated stress response (ISR) is the best characterized. Previously, we have established that the DYT- PRKRA mutations cause enhanced activation of PKR during ISR to sensitize DYT- PRKRA cells to apoptosis. In this study, we evaluate if the most prevalent substitution mutation reported in DYT- PRKRA patients alters PACT's functional role in induction of type I IFNs via the retinoic acid-inducible gene I (RIG-I) signaling. Our results indicate that the P222L mutation augments PACT's ability to induce IFN β in response to dsRNA and the basal expression of IFN β and IFN-stimulated genes (ISGs) is higher in DYT- PRKRA patient cells compared to cells from the unaffected controls. Additionally, IFN β and ISGs are also induced at higher levels in DYT- PRKRA cells in response to dsRNA. These results offer a new avenue for investigations directed towards understanding the underlying molecular pathomechanisms in DYT- PRKRA .
Keyphrases
- cell cycle arrest
- dendritic cells
- induced apoptosis
- immune response
- endoplasmic reticulum stress
- cell death
- genome wide
- oxidative stress
- binding protein
- pi k akt
- end stage renal disease
- diabetic rats
- poor prognosis
- newly diagnosed
- ejection fraction
- prognostic factors
- dna methylation
- cell proliferation
- early onset
- protein protein
- peritoneal dialysis
- transcription factor
- gene expression
- inflammatory response
- amino acid
- deep brain stimulation