Autogenous Translational Regulation of the Borna Disease Virus Negative Control Factor X from Polycistronic mRNA Using Host RNA Helicases

• DOI: 10.1371/journal.ppat.1000654
• Publication Date: 2009-11-05T22:46:59Z
• Authors: Yohei Watanabe; Naohiro Ohtaki; Yohei Hayashi; Kazuyoshi Ikuta; Keizo Tomonaga
• Keywords: Gene Expression Regulation, Viral; 0301 basic medicine; QH301-705.5; RC581-607; 3. Good health; 03 medical and health sciences; Host-Pathogen Interactions; RNA, Viral; Viral Regulatory and Accessory Proteins; Immunologic diseases. Allergy; Biology (General); Borna disease virus; RNA Helicases; Research Article

Borna disease virus (BDV) is a nonsegmented, negative-strand RNA virus that employs several unique strategies for gene expression. The shortest transcript of BDV, X/P mRNA, encodes at least three open reading frames (ORFs): upstream ORF (uORF), X, and P in the 5' to 3' direction. The X is a negative regulator of viral polymerase activity, while the P phosphoprotein is a necessary cofactor of the polymerase complex, suggesting that the translation of X is controlled rigorously, depending on viral replication. However, the translation mechanism used by the X/P polycistronic mRNA has not been determined in detail. Here we demonstrate that the X/P mRNA autogenously regulates the translation of X via interaction with host factors. Transient transfection of cDNA clones corresponding to the X/P mRNA revealed that the X ORF is translated predominantly by uORF-termination-coupled reinitiation, the efficiency of which is upregulated by expression of P. We found that P may enhance ribosomal reinitiation at the X ORF by inhibition of the interaction of the DEAD-box RNA helicase DDX21 with the 5' untranslated region of X/P mRNA, via interference with its phosphorylation. Our results not only demonstrate a unique translational control of viral regulatory protein, but also elucidate a previously unknown mechanism of regulation of polycistronic mRNA translation using RNA helicases.