DYT- PRKRA Mutation P222L Enhances PACT's Stimulatory Activity on Type I Interferon Induction.

DYT- (dystonia 16 or DYT-) is caused by mutations in the 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- mutations cause enhanced activation of PKR during ISR to sensitize DYT- cells to apoptosis. In this study, we evaluate if the most prevalent substitution mutation reported in DYT- 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- patient cells compared to cells from the unaffected controls. Additionally, IFN β and ISGs are also induced at higher levels in DYT- cells in response to dsRNA. These results offer a new avenue for investigations directed towards understanding the underlying molecular pathomechanisms in DYT-.