Resveratrol is a natural compound produced by certain plants on various stimuli. In recent years, extensive research on resveratrol has been carried out, demonstrating its capacity to prevent a wide variety of conditions, including cardiovascular diseases and cancer, and to control fungal, bacterial and viral infections. In the present review, we summarize the current knowledge of the activity of resveratrol against viral infection and describe the possible molecular pathways through which resveratrol exerts its antiviral activity.
Rotavirus genome replication and the first steps of virus morphogenesis take place in cytoplasmic viral factories, called viroplasms, containing four structural (VP1, VP2, VP3 and VP6) and two nonstructural (NSP2 and NSP5) proteins. NSP2 and NSP5 have been shown to be essential for viroplasm formation and, when co-expressed in uninfected cells, to form viroplasm-like structures (VLS). In the present work, VLS formation was shown upon co-expression of NSP5 with the core protein VP2 despite the absence of NSP2, indicating a central role for NSP5 in VLS assembly. Since VP2 and NSP2 also induce NSP5 hyperphosphorylation, the possible correlation between VLS formation and the NSP5 phosphorylation status was investigated without evidence of a direct link. In VLS induced by NSP2, the polymerase VP1 was recruited, while the middle layer protein VP6 was not, forming instead tubular structures. On the other hand, VLS induced by VP2 were able to recruit both VP1 and VP6. More importantly, in VLS formed when NSP5 was expressed with both inducers, all viroplasmic proteins were found co-localized, resembling their distribution in viroplasms. Our results suggest a key role for NSP5 in architectural assembly of viroplasms and in recruitment of viroplasmic proteins. A new role for VP2 as an inducer of viroplasms and of NSP5 hyperphosphorylation is also described. These data may contribute to the understanding of rotavirus morphogenesis.
Rotavirus morphogenesis starts in intracellular inclusion bodies called viroplasms. RNA replication and packaging are mediated by several viral proteins, of which VP1, the RNA-dependent RNA polymerase, and VP2, the core scaffolding protein, were shown to be sufficient to provide replicase activity in vitro. In vivo, however, viral replication complexes also contain the nonstructural proteins NSP2 and NSP5, which were shown to be essential for replication, to interact with each other, and to form viroplasm-like structures (VLS) when coexpressed in uninfected cells. In order to gain a better understanding of the intermediates formed during viral replication, this work focused on the interactions of NSP5 with VP1, VP2, and NSP2. We demonstrated a strong interaction of VP1 with NSP5 but only a weak one with NSP2 in cotransfected cells in the absence of other viral proteins or viral RNA. By contrast, we failed to coimmunoprecipitate VP2 with anti-NSP5 antibodies or NSP5 with anti-VP2 antibodies. We constructed a tagged form of VP1, which was found to colocalize in viroplasms and in VLS formed by NSP5 and NSP2. The tagged VP1 was able to replace VP1 structurally by being incorporated into progeny viral particles. When applying anti-tag-VP1 or anti-NSP5 antibodies, coimmunoprecipitation of tagged VP1 with NSP5 was found. Using deletion mutants of NSP5 or different fragments of NSP5 fused to enhanced green fluorescent protein, we identified the 48 C-terminal amino acids as the region essential for interaction with VP1.Rotavirus is a major etiologic agent of severe gastroenteritis in infants and young children worldwide (20,21,33). The virion (defined as a triple-layered particle [TLP]) contains a genome consisting of 11 segments of double-stranded RNA (dsRNA) and is made up of three concentric layers of proteins: the outer layer consists of the two proteins VP7 and VP4, the intermediate layer of VP6, and the internal (core) layer of VP2, with VP1 and VP3 attached at its inside as minor components (29, 41). After entry into the host cell, the virion loses the outer layer to become a double-layered particle (DLP), which is active in transcription of viral mRNAs from the dsRNA genome. The viral RNA-dependent RNA polymerase (RdRp) acts as both the transcriptase and the replicase. Several lines of evidence indicate that VP1 is the viral RdRp: (i) VP1 contains sequence motifs that are shared by RdRps of other RNA viruses (31); (ii) VP1 has NTP-binding activity and, when cross-linked with the nucleotide analog 8-azido-ATP, inhibits RNA transcription (50); (iii) VP1 specifically recognizes the 3Ј end of viral mRNAs (35); and (iv) recombinant VP1 can direct template-dependent minus-strand synthesis in vitro in the presence of VP2 (37, 54).Despite partial characterization of rotavirus replication intermediates (3,19,36,37,54), molecular details of viral genome replication and of the different steps of viral morphogenesis still remain to be elucidated. It has been shown that VP1 and VP2, the scaffolding protein of viral cores, are...
Rotavirus genomes contain 11 double-stranded (ds) RNA segments. Genome segment 11 encodes the non-structural protein NSP5 and, in some strains, also NSP6. NSP5 is produced soon after viral infection and localizes in cytoplasmic viroplasms, where virus replication takes place. RNA interference by small interfering (si) RNAs targeted to genome segment 11 mRNA of two different strains blocked production of NSP5 in a strain-specific manner, with a strong effect on the overall replicative cycle: inhibition of viroplasm formation, decreased production of other structural and non-structural proteins, synthesis of viral genomic dsRNA and production of infectious particles. These effects were shown not to be due to inhibition of NSP6. The results obtained strengthen the importance of secondary transcription/translation in rotavirus replication and demonstrate that NSP5 is essential for the assembly of viroplasms and virus replication. INTRODUCTIONRotaviruses have a genome composed of 11 segments of double-stranded RNA (dsRNA). Virus replication is entirely cytoplasmic and takes place within viroplasms, discrete structures formed at early times post-infection. The nonstructural protein NSP5, encoded by genomic segment 11, is found in viroplasms of virus-infected cells. The role of NSP5 remains to be elucidated, although a number of biochemical characteristics have been described, including its O-glycosylation, hyperphosphorylation and interaction with NSP2 and with the inner core protein VP2 (Welch et al., 1989;Chen et al., 1990;Gonzalez & Burrone, 1991;Kattoura et al., 1992Kattoura et al., , 1994Afrikanova et al., 1996Afrikanova et al., , 1998Aponte et al., 1996;Poncet et al., 1997;Taraporewala et al., 1999;Taraporewala & Patton, 2001;Eichwald et al., 2002;Berois et al., 2003). We have recently reported that NSP5 is also essential for viroplasm assembly (Vascotto et al., 2004). In some group A rotavirus strains, such as SA11, the genome segment 11 (gs11) also encodes a second nonstructural protein, termed NSP6, of 91 residues, from a different ORF (Mattion et al., 1991). In the porcine OSU strain, however, this second ORF encodes a truncated protein of 51 amino acids (ORF2) (Gonzalez & Burrone, 1989).Due in part to the lack of a reverse genetics system in rotavirus, no clear function in the viral replicative cycle has yet been found for NSP5. Here, we used the RNA interference strategy directed towards gs11 mRNA to demonstrate that NSP5 is an essential protein for the formation of viroplasms and for virus replication. METHODSCell culture and viruses. C7 and NSP2-EGFP stable cell lines were obtained and cultured as described previously (Afrikanova et al., 1996;Eichwald et al., 2004). SA11 and OSU rotaviruses were propagated in MA104 cells as described by Estes et al. (1979). Virus titres were determined by immunofluorescence on MA104 cells with anti-NSP2 antibody or by direct determination of viroplasms in the NSP2-EGFP stable cell line.Small interfering (si) RNAs and transfection. The siRNAs were chemically synthesized w...
Infection by herpesviruses causes a dramatic disturbance of PML oncogenic domains (PODs) that has been suggested to be essential for viral lytic replication. Several proteins from Kaposi's sarcoma-associated herpesvirus (KSHV) have been tested as putative POD-disrupting factors with negative results. Here, we show that LANA2, a viral protein that is absolutely required for the viability and proliferation of KSHV-infected primary effusion lymphoma (PEL) cells, increases the levels of SUMO2-ubiquitin-modified PML and induces the disruption of PODs by a proteasome-mediated mechanism. In addition, we demonstrate that this disruption is largely dependent on both the integrity of a SUMO interaction motif in LANA2 and the lysine 160 from PML. Moreover, silencing of LANA2 expression in PEL cells by RNA interference led to an increase in the PML levels. Finally, we demonstrate that LANA2 relieves PML-mediated transcriptional repression of survivin, a protein that directly contributes to malignant progression of PEL. This represents the first example of inactivation of these important antiviral structures by KSHV.
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