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TRBP control of PACT-induced phosphorylation of protein kinase R is reversed by stress.

Daher, Aicha and Laraki, Ghislaine and Singh, Madhurima and Melendez-Pena, Carlos E and Bannwarth, Sylvie and Peters, Antoine and Meurs, Eliane F and Braun, Robert E and Patel, Rekha C and Gatignol, Anne (2009) TRBP control of PACT-induced phosphorylation of protein kinase R is reversed by stress. Molecular and Cellular Biology, 29 (1). pp. 254-265. ISSN 1098-5549

Abstract

The TAR RNA binding Protein, TRBP, inhibits the activity of the interferon-induced protein kinase R (PKR), whereas the PKR activator, PACT, activates its function. TRBP and PACT also bind to each other through their double-stranded RNA binding domains (dsRBDs) and their Medipal domains, which may influence their activity on PKR. In a human immunodeficiency virus (HIV) long terminal repeat-luciferase assay, PACT unexpectedly reversed PKR-mediated inhibition of gene expression. In a translation inhibition assay in HeLa cells, PACT lacking the 13 C-terminal amino acids (PACTDelta13), but not full-length PACT, activated PKR and enhanced interferon-mediated repression. In contrast, in the astrocytic U251MG cells that express low TRBP levels, both proteins activate PKR, but PACTDelta13 is stronger. Immunoprecipitation assays and yeast two-hybrid assays show that TRBP and PACTDelta13 interact very weakly due to a loss of binding in the Medipal domain. PACT-induced PKR phosphorylation was restored in Tarbp2(-/-) murine tail fibroblasts and in HEK293T or HeLa cells when TRBP expression was reduced by RNA interference. In HEK293T and HeLa cells, arsenite, peroxide, and serum starvation-mediated stresses dissociated the TRBP-PACT interaction and increased PACT-induced PKR activation, demonstrating the relevance of this control in a physiological context. Our results demonstrate that in cells, TRBP controls PACT activation of PKR, an activity that is reversed by stress.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); but on personal or university-hosted websites only
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Date Deposited: 14 Dec 2009 13:50
Last Modified: 31 Jan 2013 01:01
URI: https://oak.novartis.com/id/eprint/986

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