期刊
BIOMOLECULES
卷 12, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/biom12050713
关键词
dystonia; DYT16; DYT-PRKRA; PACT; PRKRA; PKR; interferon; RIG-I
资金
- Dystonia Medical Research Foundation grant
- University of South Carolina ASPIRE grant
This study evaluates the functional role of the most prevalent mutation in DYT-PRKRA patients and finds that it enhances PACT's ability to induce IFN beta. These results provide a new avenue for investigating the underlying molecular mechanisms in DYT-PRKRA.
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 beta in response to dsRNA and the basal expression of IFN beta and IFN-stimulated genes (ISGs) is higher in DYT-PRKRA patient cells compared to cells from the unaffected controls. Additionally, IFN beta 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.
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