Academic Journal
A truncated PACT protein resulting from a frameshift mutation reported in movement disorder DYT16 triggers caspase activation and apoptosis
| العنوان: | A truncated PACT protein resulting from a frameshift mutation reported in movement disorder DYT16 triggers caspase activation and apoptosis |
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| المؤلفون: | Burnett, Samuel B, Vaughn, Lauren S, Strom, Joelle M, Francois, Ashley, Patel, Rekha C. |
| المساهمون: | Dystonia Medical Research Foundation |
| المصدر: | Journal of Cellular Biochemistry ; volume 120, issue 11, page 19004-19018 ; ISSN 0730-2312 1097-4644 |
| بيانات النشر: | Wiley |
| سنة النشر: | 2019 |
| المجموعة: | Wiley Online Library (Open Access Articles via Crossref) |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1002/jcb.29223 |
| الاتاحة: | http://dx.doi.org/10.1002/jcb.29223 https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fjcb.29223 https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcb.29223 https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jcb.29223 |
| Rights: | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| رقم الانضمام: | edsbas.F66C6039 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/jcb.29223 |
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