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J Biol Chem. 2015 Sep 11;290(37):22543-57. doi: 10.1074/jbc.M115.669408. Epub 2015 Jul 31.

Altered activation of protein kinase PKR and enhanced apoptosis in dystonia cells carrying a mutation in PKR activator protein PACT.

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From the University of South Carolina, Department of Biological Sciences, Columbia, South Carolina 29208.
Massachusetts General Hospital, Department of Neurology, Charlestown, Massachusetts 02129, and.
Federal University of Minas Gerais, Department of Internal Medicine, 31270-901 Belo Horizonte, MG, Brazil.
From the University of South Carolina, Department of Biological Sciences, Columbia, South Carolina 29208,


PACT is a stress-modulated activator of the interferon-induced double-stranded RNA-activated protein kinase (PKR). Stress-induced phosphorylation of PACT is essential for PACT's association with PKR leading to PKR activation. PKR activation leads to phosphorylation of translation initiation factor eIF2α inhibition of protein synthesis and apoptosis. A recessively inherited form of early-onset dystonia DYT16 has been recently identified to arise due to a homozygous missense mutation P222L in PACT. To examine if the mutant P222L protein alters the stress-response pathway, we examined the ability of mutant P222L to interact with and activate PKR. Our results indicate that the substitution mutant P222L activates PKR more robustly and for longer duration albeit with slower kinetics in response to the endoplasmic reticulum stress. In addition, the affinity of PACT-PACT and PACT-PKR interactions is enhanced in dystonia patient lymphoblasts, thereby leading to intensified PKR activation and enhanced cellular death. P222L mutation also changes the affinity of PACT-TRBP interaction after cellular stress, thereby offering a mechanism for the delayed PKR activation in response to stress. Our results demonstrate the impact of a dystonia-causing substitution mutation on stress-induced cellular apoptosis.


apoptosis; cell death; endoplasmic reticulum stress (ER stress); interferon; protein kinase RNA-activated (PKR)

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