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Viroid RNA redirects host DNA ligase 1 to act as an RNA ligase.

ABSTRACT: Viroids are a unique class of noncoding RNAs: composed of only a circular, single-stranded molecule of 246-401 nt, they manage to replicate, move, circumvent host defenses, and frequently induce disease in higher plants. Viroids replicate through an RNA-to-RNA rolling-circle mechanism consisting of transcription of oligomeric viroid RNA intermediates, cleavage to unit-length strands, and circularization. Though the host RNA polymerase II (redirected to accept RNA templates) mediates RNA synthesis and a type-III RNase presumably cleavage of Potato spindle tuber viroid (PSTVd) and closely related members of the family Pospiviroidae, the host enzyme catalyzing the final circularization step, has remained elusive. In this study we propose that PSTVd subverts host DNA ligase 1, converting it to an RNA ligase, for the final step. To support this hypothesis, we show that the tomato (Solanum lycopersicum L.) DNA ligase 1 specifically and efficiently catalyzes circularization of the genuine PSTVd monomeric linear replication intermediate opened at position G95-G96 and containing 5'-phosphomonoester and 3'-hydroxyl terminal groups. Moreover, we also show a decreased PSTVd accumulation and a reduced ratio of monomeric circular to total monomeric PSTVd forms in Nicotiana benthamiana Domin plants in which the endogenous DNA ligase 1 was silenced. Thus, in a remarkable example of parasitic strategy, viroids reprogram for their replication the template and substrate specificity of a DNA-dependent RNA polymerase and a DNA ligase to act as RNA-dependent RNA polymerase and RNA ligase, respectively.

SUBMITTER: Nohales MA

PROVIDER: S-EPMC3427106 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Viroid RNA redirects host DNA ligase 1 to act as an RNA ligase.

Nohales María-Ángeles MÁ Flores Ricardo R Daròs José-Antonio JA

Proceedings of the National Academy of Sciences of the United States of America 20120806 34

Viroids are a unique class of noncoding RNAs: composed of only a circular, single-stranded molecule of 246-401 nt, they manage to replicate, move, circumvent host defenses, and frequently induce disease in higher plants. Viroids replicate through an RNA-to-RNA rolling-circle mechanism consisting of transcription of oligomeric viroid RNA intermediates, cleavage to unit-length strands, and circularization. Though the host RNA polymerase II (redirected to accept RNA templates) mediates RNA synthesi ...[more]

PMID: 22869737

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Project description:HIV-1 modulates key host cellular pathways for successful replication and pathogenesis through viral proteins. By evaluating the hijacking of the host ubiquitination pathway by HIV-1 at the whole-cell level, we now show major perturbations in the ubiquitinated pool of the host proteins post-HIV-1 infection. Our overexpression- and infection-based studies of T cells with wild-type and mutant HIV-1 proviral constructs showed that Vpr is necessary and sufficient for reducing whole-cell ubiquitination. Mutagenic analysis revealed that the three leucine-rich helical regions of Vpr are critical for this novel function of Vpr, which was independent of its other known cellular functions. We also validated that this effect of Vpr was conserved among different subtypes (subtypes B and C) and circulating recombinants from Northern India. Finally, we establish that this phenomenon is involved in HIV-1-mediated diversion of host ubiquitination machinery specifically toward the degradation of various restriction factors during viral pathogenesis.HIV-1 is known to rely heavily on modulation of the host ubiquitin pathway, particularly for counteraction of antiretroviral restriction factors, i.e., APOBEC3G, UNG2, and BST-2, etc.; viral assembly; and release. Reports to date have focused on the molecular hijacking of the ubiquitin machinery by HIV-1 at the level of E3 ligases. Interaction of a viral protein with an E3 ligase alters its specificity to bring about selective protein ubiquitination. However, in the case of infection, multiple viral proteins can interact with this multienzyme pathway at various levels, making it much more complicated. Here, we have addressed the manipulation of ubiquitination at the whole-cell level post-HIV-1 infection. Our results show that HIV-1 Vpr is necessary and sufficient to bring about the redirection of the host ubiquitin pathway toward HIV-1-specific outcomes. We also show that the three leucine-rich helical regions of Vpr are critical for this effect and that this ability of Vpr is conserved across circulating recombinants. Our work, the first of its kind, provides novel insight into the regulation of the ubiquitin system at the whole-cell level by HIV-1.

Dataset Information

Viroid RNA redirects host DNA ligase 1 to act as an RNA ligase.

Publications

Viroid RNA redirects host DNA ligase 1 to act as an RNA ligase.

Similar Datasets

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