Biomolecules (May 2022)

DYT-<i>PRKRA</i> Mutation P222L Enhances PACT’s Stimulatory Activity on Type I Interferon Induction

  • Lauren S. Vaughn,
  • Kenneth Frederick,
  • Samuel B. Burnett,
  • Nutan Sharma,
  • D. Cristopher Bragg,
  • Sarah Camargos,
  • Francisco Cardoso,
  • Rekha C. Patel

DOI
https://doi.org/10.3390/biom12050713
Journal volume & issue
Vol. 12, no. 5
p. 713

Abstract

Read online

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.

Keywords