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Suppression of human T-cell leukemia virus I gene expression by pokeweed antiviral protein.

ABSTRACT: Human T-cell leukemia virus I (HTLV-I) is a deltaretrovirus that is the causative agent of adult T-cell leukemia and the neurological disorder HTLV-I-associated myelopathy/tropical spastic paraparesis. Currently, no effective antiretroviral treatment options are available to restrict the development of diseases associated with the virus. In this work, we investigated the activity of pokeweed antiviral protein (PAP) on HTLV-I, when expressed from a proviral clone in 293T cells or in an HTLV-I immortalized cell line. PAP is a plant-derived N-glycosidase that exhibits antiviral activity against a number of viruses; however, its mode of action has not been clearly defined. Here, we describe the mechanism by which PAP inhibited production of HTLV-I. We show that PAP depurinated nucleotides within the gag open reading frame and suppressed the synthesis of viral proteins in part by decreasing the translational efficiency of HTLV-I gag/pol mRNA. Observed reduction in levels of viral mRNAs were not due to enhanced degradation; rather, decreased amounts of viral transactivator protein, Tax, led to feed-back inhibition of transcription from the viral promoter. Therefore, PAP efficiently suppressed HTLV-I gene expression at both translational and transcriptional levels, resulting in substantially diminished virus production. Significantly, no changes in viability or rates of cellular transcription or translation were observed in cells expressing PAP, indicating that this protein was not toxic. Antiviral activity, together with the absence of cytotoxicity, supports further investigation of this enzyme as a novel therapeutic agent against the progression of HTLV-I infection.

SUBMITTER: Mansouri S

PROVIDER: S-EPMC2781541 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Suppression of human T-cell leukemia virus I gene expression by pokeweed antiviral protein.

Mansouri Sheila S Choudhary Gunjan G Sarzala Paulina M PM Ratner Lee L Hudak Katalin A KA

The Journal of biological chemistry 20090911 45

Human T-cell leukemia virus I (HTLV-I) is a deltaretrovirus that is the causative agent of adult T-cell leukemia and the neurological disorder HTLV-I-associated myelopathy/tropical spastic paraparesis. Currently, no effective antiretroviral treatment options are available to restrict the development of diseases associated with the virus. In this work, we investigated the activity of pokeweed antiviral protein (PAP) on HTLV-I, when expressed from a proviral clone in 293T cells or in an HTLV-I imm ...[more]

PMID: 19748897

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Project description:Ribosome-inactivating proteins (RIPs) are RNA glycosidases thought to function in defense against pathogens. These enzymes remove purine bases from RNAs, including rRNA; the latter activity decreases protein synthesis in vitro, which is hypothesized to limit pathogen proliferation by causing host cell death. Pokeweed antiviral protein (PAP) is a RIP synthesized by the American pokeweed plant (Phytolacca americana). PAP inhibits virus infection when expressed in crop plants, yet little is known about the function of PAP in pokeweed due to a lack of genomic tools for this non-model species. In this work, we de novo assembled the pokeweed genome and annotated protein-coding genes. Sequencing comprised paired-end reads from a short-insert library of 83X coverage, and our draft assembly (N50 = 42.5 Kb) accounted for 74% of the measured pokeweed genome size of 1.3 Gb. We obtained 29,773 genes, 73% of which contained known protein domains, and identified several PAP isoforms. Within the gene models of each PAP isoform, a long 5' UTR intron was discovered, which was validated by RT-PCR and sequencing. Presence of the intron stimulated reporter gene expression in tobacco. To gain further understanding of PAP regulation, we complemented this genomic resource with expression profiles of pokeweed plants subjected to stress treatments [jasmonic acid (JA), salicylic acid, polyethylene glycol, and wounding]. Cluster analysis of the top differentially expressed genes indicated that some PAP isoforms shared expression patterns with genes involved in terpenoid biosynthesis, JA-mediated signaling, and metabolism of amino acids and carbohydrates. The newly sequenced promoters of all PAP isoforms contained cis-regulatory elements associated with diverse biotic and abiotic stresses. These elements mediated response to JA in tobacco, based on reporter constructs containing promoter truncations of PAP-I, the most abundant isoform. Taken together, this first genomic resource for the Phytolaccaceae plant family provides new insight into the regulation and function of PAP in pokeweed.

Dataset Information

Suppression of human T-cell leukemia virus I gene expression by pokeweed antiviral protein.

Publications

Suppression of human T-cell leukemia virus I gene expression by pokeweed antiviral protein.

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