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

Abstract

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.

• Authors: Lauren S Vaughn, Kenneth Frederick, Samuel B Burnett, Nutan Sharma, D Cristopher Bragg, Sarah Camargos, Francisco Cardoso, Rekha C Patel
• Journal: Biomolecules (Biomolecules) Vol. 12 Issue 5 (05 17 2022) ISSN: 2218-273X [Electronic] Switzerland
• PMID: 35625640 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interferon Type I
• PRKRA protein, human
• RNA, Double-Stranded
• RNA-Binding Proteins
• eIF-2 Kinase

Topics

• Dystonic Disorders
• Humans
• Interferon Type I (genetics, metabolism)
• Mutation
• RNA, Double-Stranded (genetics)
• RNA-Binding Proteins (genetics, metabolism)
• eIF-2 Kinase (genetics, metabolism)