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A truncated PACT protein resulting from a frameshift mutation reported in movement disorder DYT16 triggers caspase activation and apoptosis
Author(s) -
Burnett Samuel B,
Vaughn Lauren S,
Strom Joelle M,
Francois Ashley,
Patel Rekha C.
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.29223
Subject(s) - protein kinase r , pact , unfolded protein response , eif 2 kinase , microbiology and biotechnology , biology , protein kinase a , mutant protein , autophagy related protein 13 , mutant , phosphorylation , endoplasmic reticulum , protein phosphorylation , genetics , mitogen activated protein kinase kinase , cyclin dependent kinase 2 , history , archaeology , gene
P rotein Act ivator (PACT) activates the interferon (IFN)‐induced double‐stranded (ds) RNA‐activated protein kinase (PKR) in response to stress signals. Oxidative stress and endoplasmic reticulum (ER) stress causes PACT‐mediated PKR activation, which leads to phosphorylation of translation initiation factor eIF2α, inhibition of protein synthesis, and apoptosis. A dominantly inherited form of early‐onset dystonia 16 (DYT16) has been identified to arise due to a frameshift (FS) mutation in PACT. To examine the effect of the resulting truncated mutant PACT protein on the PKR pathway, we examined the biochemical properties of the mutant protein and its effect on mammalian cells. Our results indicate that the FS mutant protein loses its ability to bind dsRNA as well as its ability to interact with PKR while surprisingly retaining the ability to interact with PACT and PKR‐inhibitory protein TRBP. The truncated FS mutant protein, when expressed as a fusion protein with a N‐terminal fluorescent mCherry tag aggregates in mammalian cells to induce apoptosis via activation of caspases both in a PKR‐ and PACT‐dependent as well as independent manner. Our results indicate that interaction of FS mutant protein with PKR inhibitor TRBP can dissociate PACT from the TRBP‐PACT complex resulting in PKR activation and consequent apoptosis. These findings are relevant to diseases resulting from protein aggregation especially since the PKR activation is a characteristic of several neurodegenerative conditions.