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.

Antisense lncRNA CHROMR is linked to glioma patient survival

“…Glioma cells are able to evade the anti-tumor immune response due to the cancer’s immunosuppressive repertoire ( Chen et al, 2021 ). Since PRKRA is known to play a role in antiviral response ( Vaughn et al, 2022 ), perhaps our observations of high levels of CHROMR in glioma could play a role in inhibiting PRKRA related antiviral (which is related to anti-tumor) response. This would, however, require functional experiments to prove.…”

“…Protein coding PRKRA is important for normal brain function. Mutations of the PRKRA gene are responsible for the DYT-PRKRA (DYT16) dystonia ( Camargos et al, 2008 ; Burnett et al, 2020 ; Vaughn et al, 2022 ), characterized by death of neurons in specific brain regions, causing involuntary movements. This effect comes from aberrant and increased stress response ( Vaughn et al, 2022 ).…”

“…Mutations of the PRKRA gene are responsible for the DYT-PRKRA (DYT16) dystonia ( Camargos et al, 2008 ; Burnett et al, 2020 ; Vaughn et al, 2022 ), characterized by death of neurons in specific brain regions, causing involuntary movements. This effect comes from aberrant and increased stress response ( Vaughn et al, 2022 ). Perhaps there is aberrant PRKRA protein function in glioma cells, resulting in a reduced ability to respond to pro-apoptotic signals, that could be caused by the observed high CHROMR expression in gliomas.…”

“…PRKRA has been implicated in conferring chemoresistance to mucinous ovarian cancer cells ( Hisamatsu et al, 2019 ) and in antiviral response ( Vaughn et al, 2022 ). It is still to be determined if PRKRA acts in a similar fashion in glioma as it does the mucinous ovarian cancer cells, as gliomas are notoriously resistant to chemotherapeutic agents.…”

The crucial regulatory role of type I interferon in inflammatory diseases

“…In this process, the protein activator of the interferon-induced protein kinase (PACT), also referred to as the protein kinase, interferon-inducible double-stranded RNA-dependent activator (PRKRA), is a crucial component in initiating and maintaining RIG-I-dependent antiviral responses [ 165 ]. PACT physically binds to the C-terminal repression domain of RIG-I and then enhances the activation of RIG-I through poly (I:C) of intermediate length [ 166 , 167 ]. Afterward, RIG-I functions as a virus sensor that triggers the innate antiviral response and could be activated by dsRNA [ 168 ].…”