Resistance of Human Hepatitis Delta Virus RNAs to Dicer Activity

Chang, Jinhong; Provost, Patrick; Taylor, John M.

doi:10.1128/jvi.77.22.11910-11917.2003

Cited by 58 publications

(42 citation statements)

References 55 publications

(54 reference statements)

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“…Thus, there is a solid basis for a structured PSTVd RNA to serve as a DCL substrate in vivo. It should be noted that a previous study showed that the plus-PSTVd RNA was resistant to cleavage by human dicer (15). Whether this is attributed to some differences in the biochemical activities of human and plant dicers or in technical procedures is unknown.…”

Section: Discussionmentioning

confidence: 98%

A Structured Viroid RNA Serves as a Substrate for Dicer-Like Cleavage To Produce Biologically Active Small RNAs but Is Resistant to RNA-Induced Silencing Complex-Mediated Degradation

Itaya¹,

Zhong²,

Bundschuh

et al. 2007

J Virol

185

177

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RNA silencing is a potent means of antiviral defense in plants and animals. A hallmark of this defense response is the production of 21-to 24-nucleotide viral small RNAs via mechanisms that remain to be fully understood. Many viruses encode suppressors of RNA silencing, and some viral RNAs function directly as silencing suppressors as counterdefense. The occurrence of viroid-specific small RNAs in infected plants suggests that viroids can trigger RNA silencing in a host, raising the question of how these noncoding and unencapsidated RNAs survive cellular RNA-silencing systems. We address this question by characterizing the production of small RNAs of Potato spindle tuber viroid (srPSTVds) and investigating how PSTVd responds to RNA silencing. Our molecular and biochemical studies provide evidence that srPSTVds were derived mostly from the secondary structure of viroid RNAs. Replication of PSTVd was resistant to RNA silencing, although the srPSTVds were biologically active in guiding RNA-induced silencing complex (RISC)-mediated cleavage, as shown with a sensor system. Further analyses showed that without possessing or triggering silencing suppressor activities, the PSTVd secondary structure played a critical role in resistance to RISC-mediated cleavage. These findings support the hypothesis that some infectious RNAs may have evolved specific secondary structures as an effective means to evade RNA silencing in addition to encoding silencing suppressor activities. Our results should have important implications in further studies on RNA-based mechanisms of host-pathogen interactions and the biological constraints that shape the evolution of infectious RNA structures.A major focus of current biology is to understand how a pathogen has evolved mechanisms to achieve a balance among several interrelated activities that are crucial to establish a full infection: evading or suppressing host defense, minimizing destructive interference of host metabolism, and maximizing utilization of host factors to support replication and systemic spread. A full understanding of these mechanisms is not only necessary to build a foundation for developing technologies to combat pathogen diseases but also can provide fundamental mechanistic insights into the regulation of basic cellular processes.Recent studies have discovered small RNA-mediated gene silencing as a powerful antiviral mechanism in plants and animals (6,22,25,47,49,50,72,77,84,(87)(88)(89)98). Furthermore, small RNA-mediated gene silencing plays essential roles in regulating a wide variety of growth and development processes (4-6, 11, 13, 17, 23, 28, 42). A key mediator of RNA silencing is several classes of 21-to 24-nucleotide (nt) small RNAs.MicroRNAs (miRNAs) are produced by cleavage of hairpin RNA precursors encoded by the genome of an organism. Short interfering RNAs (siRNAs) are generated by cleavage of double-stranded RNAs (dsRNAs) that may originate from several sources, including cellular genomes, viral replication intermediates, aberrant cellular RNAs, overexpresse...

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Section: Discussionmentioning

confidence: 98%

A Structured Viroid RNA Serves as a Substrate for Dicer-Like Cleavage To Produce Biologically Active Small RNAs but Is Resistant to RNA-Induced Silencing Complex-Mediated Degradation

Itaya¹,

Zhong²,

Bundschuh

et al. 2007

J Virol

185

177

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“…The hepatitis delta virus genome is largely but not completely duplex RNA. While it can be edited in a site-selective manner by ADAR and can activate PKR (48, 313), it cannot be cleaved by Dicer (43). On the other hand, fragile X syndrome transcripts encode trinucleotide repeats that can form RNA hairpins that cannot activate PKR but are efficiently cut by Dicer (122).…”

Section: Vol 68 2004mentioning

confidence: 99%

Effects of Length and Location on the Cellular Response to Double-Stranded RNA

Wang

Carmichael

2004

Microbiol Mol Biol Rev

106

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Since double-stranded RNA (dsRNA) has not until recently generally been thought to be deliberately expressed in cells, it has commonly been assumed that the major source of cellular dsRNA is viral infections. In this view, the cellular responses to dsRNA would be natural and perhaps ancient antiviral responses. While the cell may certainly react to some dsRNAs as an antiviral response, this does not represent the only response or even, perhaps, the major one. A number of recent observations have pointed to the possibility that dsRNA molecules are not seen only as evidence of viral infection or recognized for degradation because they cannot be translated. In some instances they may also play important roles in normal cell growth and function. The purpose of this review is to outline our current understanding of the fate of dsRNA in cells, with a focus on the apparent fact that their fates and functions appear to depend critically not only on where in the cell dsRNA molecules are found, but also on how long they are and perhaps on how abundant they are

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“…This would be sufficient to protect them against cleavage by Dicer, which requires a minimum of Ϸ19 bp of dsRNA (46). Several recent observations support a direct role of secondary RNA structures in conferring resistance to RNA silencing: (i) regions of a plant mRNA that have the potential to form duplex structure have been shown to accumulate in cells where the mRNA is silenced (47), (ii) a short defective interfering viral RNA, with the potential to form a stable secondary structure, is significantly more resistant to RNA silencing than is its helper virus (48), and (iii) PSTVd or viroid-like RNAs are highly resistant to Dicer cleavage in an in vitro system (49).…”

Section: Does Rna Silencing Mediate the Evolution Of Viroids And Viralmentioning

confidence: 99%

On the role of RNA silencing in the pathogenicity and evolution of viroids and viral satellites

Wang

Bian

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

267

233

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Viroids and most viral satellites have small, noncoding, and highly structured RNA genomes. How they cause disease symptoms without encoding proteins and why they have characteristic secondary structures are two longstanding questions. Recent studies have shown that both viroids and satellites are capable of inducing RNA silencing, suggesting a possible role of this mechanism in the pathology and evolution of these subviral RNAs. Here we show that preventing RNA silencing in tobacco, using a silencing suppressor, greatly reduces the symptoms caused by the Y satellite of cucumber mosaic virus. Furthermore, tomato plants expressing hairpin RNA, derived from potato spindle tuber viroid, developed symptoms similar to those of potato spindle tuber viroid infection. These results provide evidence suggesting that viroids and satellites cause disease symptoms by directing RNA silencing against physiologically important host genes. We also show that viroid and satellite RNAs are significantly resistant to RNA silencing-mediated degradation, suggesting that RNA silencing is an important selection pressure shaping the evolution of the secondary structures of these pathogens.V iroids and most viral satellites, which are the smallest known infectious agents in plants, have single-stranded RNA genomes of 200-400 nt and do not encode proteins (1-3). Whereas viroids replicate autonomously by using host-encoded RNA polymerase, satellite RNAs multiply only in the presence of a helper virus that provides the appropriate RNA-dependent RNA polymerase (2, 4). Intriguingly, some viroids and satellites can induce unique, highly host species-specific disease symptoms despite their exceedingly small size and lack of mRNA activity. Previous studies have shown that one, or a few, nucleotide changes in their RNA genomes can dramatically alter the virulence of these subviral RNAs or the host-plant specificity of the disease symptoms (5-7). Despite intensive investigation, major questions remain as to how these minor sequence variations modulate viroid and satellite pathology and how host plants develop symptoms in response to specific sequences. A striking similarity among viroids and small satellites is that they tend to form characteristic secondary structures due to intramolecular base-pairing. These structures are clearly important, because the evolution of these small RNAs appears to be constrained by the need to preserve their distinct structural features. However, the host factor(s) that imposes this evolutionary pressure has yet to be identified.RNA silencing is a sequence-specific RNA degradation process directed by double-stranded RNA (dsRNA) or selfcomplementary hairpin RNA (hpRNA). This dsRNA or hpRNA is cleaved by an RNase III-like enzyme known as Dicer to generate small (21-to 25-nt) RNAs, termed small interfering RNAs (siRNAs), which are used to guide siRNAribonuclease complexes [known as RNA-induced silencing complexes (RISC)] to degrade cognate single-stranded RNA (8). Recent studies have shown that plants infected with pota...

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Resistance of Human Hepatitis Delta Virus RNAs to Dicer Activity

Cited by 58 publications

References 55 publications

A Structured Viroid RNA Serves as a Substrate for Dicer-Like Cleavage To Produce Biologically Active Small RNAs but Is Resistant to RNA-Induced Silencing Complex-Mediated Degradation

A Structured Viroid RNA Serves as a Substrate for Dicer-Like Cleavage To Produce Biologically Active Small RNAs but Is Resistant to RNA-Induced Silencing Complex-Mediated Degradation

Effects of Length and Location on the Cellular Response to Double-Stranded RNA

On the role of RNA silencing in the pathogenicity and evolution of viroids and viral satellites

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