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Structural and mechanistic aspects of 3C proteases from the Picornavirus family.

Picornavirus 3C proteases are prime targets for rational drug design. This viral protease appears in a large number of viruses from the Picornavirus family that cause serious disease syndromes, and it has an important role in the life cycle of the virus, processing the translation product of the Picornavirus genome by progressive co- and posttranslational cleavages. It is, therefore, important to gain structural and mechanistic information about this family of enzymes. We concentrate in this paper on the specific features of the 3C; particularly, we are trying to show that the 3C constitute a new family to enzymes which is neither a serine- nor a cysteine-type protease. General basic theory on the behavior of sulfur nucleophile vs the behavior of oxygen nucleophile regarding the nucleophilic attack on carbonyl compounds and the possible determinants in the structure of 3C viral proteases of rhinovirus 1A are being discussed.

3C Viral Proteases↗

PubMed2002

VPg unlinkase, the phosphodiesterase that hydrolyzes the bond between VPg and picornavirus RNA: a minimal nucleic moiety of the substrate.

VPg unlinkase is an unusual eukaryotic enzyme that catalyzes hydrolysis of the phosphodiester bond between residues of the unique tyrosine of VPg (viral protein genome-linked) and the 5;-terminal uridylic acid of picornavirus RNA. Cellular targets of the VPg unlinking enzyme are yet unknown. To determine an essential nucleic part of the covalent linkage unit that is necessary for the VPg unlinkase reaction, the following derivatives of the encephalomyocarditis virus (EMCV) VPg-RNA complex were used: [125I]Kp-pUpUpGp, [125I]Kp-pUp, and [125I]Kp-pU (Kp is residual peptides bound to RNA after proteinase K treatment of VPg-RNA). [125I]K-peptides were unlinked from [125I]Kp-pUpUpGp and [125I]Kp-RNA with similar velocity, but [125I]Kp-pUp was split much slower. Under the same conditions [125I]Kp-pU was not dissociated at all. Thus, pUp is a minimal part of picornavirus RNA that is necessary for VPg unlinkase. We speculate that cellular substrates of the enzyme are phosphodiesters of oligo(poly)ribonucleotides and tyrosine or tyrosine peptides. In no case [125I]VPg-pU, [125I]VPg-pUp, and [125I]VPg-pUpUpGp were hydrolyzed by VPg unlinkase, in contrast with [125I]VPg-RNA and [125I]VPg-pUpUpGpApApApGp. We conclude that the whole VPg, when bound to trinucleotide (but not to heptanucleotide), protects the inter-polymeric phosphodiester bond against hydrolysis of the covalent linkage unit. We speculate that VPg unlinkase might repair covalent complexes of RNA and topoisomerases and trigger degradation process of the picornavirus RNA.

Animals↗

PubMed2026

Redox cycling of viral RNA polymerase controls picornavirus replication.

Picornaviruses, including foot-and-mouth disease virus (FMDV), enterovirus 71 (EV71) and encephalomyocarditis virus (EMCV), are important pathogens that cause fever, herpes, and myocarditis in humans and animals. The interplay between picornaviruses and their hosts remains enigmatic. Here we perform porcine genome-wide CRISPR/Cas9 screens and identify methionine sulfoxide reductase B3 (MSRB3) as an essential factor for FMDV. MSRB3 deficiency inhibits FMDV replication. Mechanistically, MSRB3 eliminates methionine oxidation of FMDV 3D polymerase and stabilizes its expression. Further studies show that radical SAM domain-containing protein 1 (RSAD1) catalyzes methionine oxidation of FMDV 3D polymerase and promotes its aggregation and subsequent degradation through the autophagy-lysosome pathway. Importantly, RSAD1-MSRB3-mediated redox modification also affects the stability of 3D polymerases of EV71 and EMCV, and regulates their infectivity and pathogenesis both in vitro and in vivo. Collectively, this study corroborates that RSAD1-MSRB3-mediated redox cycling of 3D polymerase plays a conserved function in modulating picornavirus infection, providing insights into viral pathogenesis and broad-spectrum antiviral development.

Animals↗

PubMed1996

Equine rhinovirus 1 is more closely related to foot-and-mouth disease virus than to other picornaviruses.

Equine rhinovirus 1 (ERhV1) is a respiratory pathogen of horses which has an uncertain taxonomic status. We have determined the nucleotide sequence of the ERhV1 genome except for a small region at the 5' end. The predicted polyprotein was encoded by 6741 nucleotides and possessed a typical picornavirus proteolytic cleavage pattern, including a leader polypeptide. The genomic structure and predicted amino acid sequence of ERhV1 were more similar to those of foot-and-mouth disease viruses (FMDVs), the only members of the aphthovirus genus, than to those of other picornaviruses. Features which were most similar to FMDV included a 16-amino acid 2A protein which was 87.5% identical in sequence of FMDV 2A, a leader (L) protein similar in size to FMDV Lab and the possibility of a truncated L protein similar in size to FMDV Lb, and a 3C protease which recognizes different cleavage sites. However, unlike FMDV, ERhV1 had only one copy of the 3B (VPg) polypeptide. The phylogenetic relationships of the ERhV1 sequence and nucleotide sequences of representative species of the five genera of the family Picornaviridae were examined. Nucleotide sequences coding for the complete polyprotein, the RNA polymerase, and VP1 were analyzed separately. The phylogenetic trees confirmed that ERhV1 was more closely related to FMDV than to other picornaviruses and suggested that ERhV1 may be a member, albeit very distant, of the aphthovirus genus.

Amino Acid Sequence↗

PubMed1989

Polymerase chain reaction for human picornaviruses.

We have used enzymic amplification of specific nucleic acid sequences followed by hybridization, for the rapid detection and typing of human picornaviruses after cell culture isolation. The test is based on the synthesis of cDNA, the polymerase chain reaction and the use of oligonucleotide probes. The primers were selected from the 5' non-coding region of the genome representing highly conserved regions. Sequences specific to enteroviruses and rhinoviruses were used as probes. The assay was able to identify all the picornavirus reference strains analysed and it was also possible to discriminate between enteroviruses and rhinoviruses by the hybridization procedure. When 29 picornavirus clinical isolates were analysed, all except one were detected by gel electrophoresis and a specific hybridization signal was obtained with all except three strains using the oligonucleotide probes.

Base Sequence↗

PubMed2000

The 2A proteins of three diverse picornaviruses are related to each other and to the H-rev107 family of proteins involved in the control of cell proliferation.

The 2A protein appears to be diverse among picornaviruses, in contrast to the other non-structural proteins, which have homologous structures and functions. In enteroviruses and rhinoviruses, 2A is a trypsin-like protease involved in protein processing and in shut-off of host-cell macromolecular synthesis. The aphthovirus and cardiovirus 2A is associated with an unusual processing event at the 2A/2B junction. It is shown here that the 2A protein of several diverse picornaviruses, the human parechoviruses, Aichi virus and avian encephalomyelitis virus, possess previously unrecognized conserved motifs and are likely to have a common function. Moreover, these motifs, a conserved histidine and flanking amino acids, an asparagine-cysteine dipeptide and a putative transmembrane domain, are characteristic of a family of cellular proteins, at least two of which are involved in the control of cell growth. These observations have important implications for an understanding of picornavirus genome structure and evolution, as well as pointing to possible functions of 2A in these viruses.

Amino Acid Sequence↗

PubMed2006

Formerly unclassified, acid-stable equine picornaviruses are a third equine rhinitis B virus serotype in the genus Erbovirus.

Acid-stable equine picornaviruses (ASPs) were identified as a distinct serotype of equine picornaviruses that were isolated from nasal swabs taken from horses with acute febrile respiratory disease in the UK and Japan, and were placed in the group of unclassified picornaviruses. The nucleotide sequence of the P1 region, encoding the capsid proteins, was determined for three ASP isolates from the UK and the sequences were aligned with published sequences of Equine rhinitis B virus (ERBV), genus Erbovirus, including acid-labile ERBV1 and ERBV2 and the recently identified acid-stable ERBV1. The ASPs belong to the same phylogenetic group, composed of five acid-stable ERBV1 isolates. ERBV1 rabbit antiserum neutralized the ASP isolates at approximately 1/10 titre relative to acid-stable and acid-labile ERBV1 isolates, supporting prior findings that ASPs are a distinct serotype, albeit cross-neutralizing weakly with ERBV1. The genus Erbovirus therefore presently comprises three serotypes: ERBV1, ERBV2 and the proposed ERBV3.

Acids↗

PubMed1966

Comparative study of seven picornaviruses of man.

Jamison, Richard M. (Baylor University College of Medicine, Houston, Tex.), and Heather D. Mayor. Comparative study of seven picornaviruses of man. J. Bacteriol. 91:1971-1976. 1966.-The buoyant densities in CsCl and potassium tartrate of seven acid-resistant picornaviruses of man were determined. The viruses studied were found to be a relatively homogeneous group. Buoyant densities ranged from 1.32 to 1.35 g/cc in CsCl and 1.21 to 1.23 g/cc in potassium tartrate. The buoyant density of each virus did not vary by more than 0.01 g/cc. The host cell of origin and passage level did not influence the buoyant density of the virions. However, measurements of the diameters of purified virions by a standard method have shown that there are considerable size variations among these picornaviruses. The diameters ranged from 18 to 25 mmu. Echovirus 19 and poliovirus 1 were significantly larger (mean diameter, 23.5 mmu) than echoviruses 4, 6, 16, and 23, and coxsackievirus B2 (mean diameter, 21.0 mmu).

Enterovirus↗

PubMed2005

Detection of human picornaviruses by multiplex reverse transcription-PCR and liquid hybridization.

A qualitative multiplex reverse transcription (RT)-PCR and liquid hybridization assay for the detection of human enteroviruses, rhinoviruses, parechoviruses, and Aichi virus was developed. Furthermore, a separate assay for the recognition of hepatitis A virus was established to complement the test pattern so that all human picornaviruses were covered. The amplicons, which represented the 5' untranslated regions of the viral RNA genomes, were identified in liquid hybridization reactions with genus-specific digoxigenin-labeled oligonucleotide probes. The sensitivity of the multiplex RT-PCR and liquid hybridization assay was 10 to 100 picornavirus genome equivalents for representatives of each picornavirus genus. The hepatitis A virus assay exhibited a sensitivity of 10 genome copies. Both the uniplex and the multiplex tests were highly specific for the target viruses. Twenty-three clinical samples, including cerebrospinal fluid, serum, and nasopharyngeal swab specimens, were used for clinical evaluation of the multiplex RT-PCR assay. The results obtained were consistent with the results of routine virus diagnostic assays. Furthermore, the assay was used to screen 68 stool specimens for the presence of parechoviruses and Aichi virus. One sample was found to contain parechovirus RNA, whereas no Aichi virus was detected. The assay described here can be applied for the efficient identification of human enteroviruses and rhinoviruses in clinical specimens and simultaneously enables the collection of information on the epidemiology and clinical outcomes of infections caused by the currently poorly known human parechoviruses and Aichi virus.

Humans↗

PubMed2006

Effects of picornavirus 3A Proteins on Protein Transport and GBF1-dependent COP-I recruitment.

The 3A protein of the coxsackievirus B3 (CVB3), an enterovirus that belongs to the family of the picornaviruses, inhibits endoplasmic reticulum-to-Golgi transport. Recently, we elucidated the underlying mechanism by showing that CVB3 3A interferes with ADP-ribosylation factor 1 (Arf1)-dependent COP-I recruitment to membranes by binding and inhibiting the function of GBF1, a guanine nucleotide exchange factor that is required for the activation of Arf1 (E. Wessels et al., Dev. Cell 11:191-201, 2006). Here, we show that the 3A protein of poliovirus, another enterovirus, is also able to interfere with COP-I recruitment through the same mechanism. No interference with protein transport or COP-I recruitment was observed for the 3A proteins of any of the other picornaviruses tested here (human rhinovirus [HRV], encephalomyocarditis virus, foot-and-mouth disease virus, and hepatitis A virus). We show that the 3A proteins of HRV, which are the most closely related to the enteroviruses, are unable to inhibit COP-I recruitment, due to a reduced ability to bind GBF1. When the N-terminal residues of the HRV 3A proteins are replaced by those of CVB3 3A, chimeric proteins are produced that have gained the ability to bind GBF1 and, by consequence, to inhibit protein transport. These results show that the N terminus of the CVB3 3A protein is important for binding of GBF1 and its transport-inhibiting function. Taken together, our data demonstrate that the activity of the enterovirus 3A protein to inhibit GBF1-dependent COP-I recruitment is unique among the picornaviruses.

Animals↗

PubMed2002

Unique characteristics of a picornavirus internal ribosome entry site from the porcine teschovirus-1 talfan.

The teschoviruses constitute a recently defined picornavirus genus. Most of the genome sequence of the porcine teschovirus-1 (PTV) Talfan and several other strains is known. We now demonstrate that initiation of protein synthesis occurs at nucleotide (nt) 412 on the PTV Talfan RNA and that nt 1 to 405 contains an internal ribosome entry site (IRES) that functions efficiently in vitro and within mammalian cells. In comparison with other picornavirus IRES elements, the PTV IRES is relatively short and lacks a significant polypyrimidine tract near the 3' end. Expression of an enterovirus 2A protease, which induces cleavage of eIF4G within the translation initiation complex eIF4F, has little effect on the PTV IRES activity within BHK cells. The PTV IRES has a unique set of properties and represents a new class of picornavirus IRES element.

5' Untranslated Regions↗

PubMed2003

The 5'-end sequence of the genome of Aichi virus, a picornavirus, contains an element critical for viral RNA encapsidation.

Picornavirus positive-strand RNAs are selectively encapsidated despite the coexistence of viral negative-strand RNAs and cellular RNAs in infected cells. However, the precise mechanism of the RNA encapsidation process in picornaviruses remains unclear. Here we report the first identification of an RNA element critical for encapsidation in picornaviruses. The 5' end of the genome of Aichi virus, a member of the family Picornaviridae, folds into three stem-loop structures (SL-A, SL-B, and SL-C, from the most 5' end). In the previous study, we constructed a mutant, termed mut6, by exchanging the seven-nucleotide stretches of the middle part of the stem in SL-A with each other to maintain the base pairings of the stem. mut6 exhibited efficient RNA replication and translation but formed no plaques. The present study showed that in cells transfected with mut6 RNA, empty capsids were accumulated, but few virions containing RNA were formed. This means that mut6 has a severe defect in RNA encapsidation. Site-directed mutational analysis indicated that as the mutated region was narrowed, the encapsidation was improved. As a result, the mutation of the 7 bp of the middle part of the stem in SL-A was required for abolishing the plaque-forming ability. Thus, the 5'-end sequence of the Aichi virus genome was shown to play an important role in encapsidation.

5' Untranslated Regions↗

PubMed2005

The polypyrimidine tract binding protein is required for efficient picornavirus gene expression and propagation.

Mammalian host factors required for efficient viral gene expression and propagation have been often recalcitrant to genetic analysis. A case in point is the function of cellular factors that trans-activate internal ribosomal entry site (IRES)-driven translation, which is operative in many positive-stranded RNA viruses, including all picornaviruses. These IRES trans-acting factors have been elegantly studied in vitro, but their in vivo importance for viral gene expression and propagation has not been widely confirmed experimentally. Here we use RNA interference to deplete mammalian cells of one such factor, the polypyrimidine tract binding protein, and test its requirement in picornavirus gene expression and propagation. Depletion of the polypyrimidine tract binding protein resulted in a marked delay of particle propagation and significantly decreased synthesis and accumulation of viral proteins of poliovirus and encephalomyocarditis virus. These effects could be partially restored by expression of an RNA interference-resistant exogenous polypyrimidine tract binding protein. These data indicate a critical role for the polypyrimidine tract binding protein in picornavirus gene expression and strongly suggest a requirement for efficient IRES-dependent translation.

DNA-Binding Proteins↗

PubMed2001

Eukaryotic initiation factor 4G-poly(A) binding protein interaction is required for poly(A) tail-mediated stimulation of picornavirus internal ribosome entry segment-driven translation but not for X-mediated stimulation of hepatitis C virus translation.

Efficient translation of most eukaryotic mRNAs results from synergistic cooperation between the 5' m(7)GpppN cap and the 3' poly(A) tail. In contrast to such mRNAs, the polyadenylated genomic RNAs of picornaviruses are not capped, and translation is initiated internally, driven by an extensive sequence termed IRES (for internal ribosome entry segment). Here we have used our recently described poly(A)-dependent rabbit reticulocyte lysate cell-free translation system to study the role of mRNA polyadenylation in IRES-driven translation. Polyadenylation significantly stimulated translation driven by representatives of each of the three types of picornaviral IRES (poliovirus, encephalomyocarditis virus, and hepatitis A virus, respectively). This did not result from a poly(A)-dependent alteration of mRNA stability in our in vitro translation system but was very sensitive to salt concentration. Disruption of the eukaryotic initiation factor 4G-poly(A) binding protein (eIF4G-PABP) interaction or cleavage of eIF4G abolished or severely reduced poly(A) tail-mediated stimulation of picornavirus IRES-driven translation. In contrast, translation driven by the flaviviral hepatitis C virus (HCV) IRES was not stimulated by polyadenylation but rather by the authentic viral RNA 3' end: the highly structured X region. X region-mediated stimulation of HCV IRES activity was not affected by disruption of the eIF4G-PABP interaction. These data demonstrate that the protein-protein interactions required for synergistic cooperativity on capped and polyadenylated cellular mRNAs mediate 3'-end stimulation of picornaviral IRES activity but not HCV IRES activity. Their implications for the picornavirus infectious cycle and for the increasing number of identified cellular IRES-carrying mRNAs are discussed.

5' Untranslated Regions↗

PubMed1975

An epidemic of picornavirus and adenovirus conjunctivitis.

A pandemic of acute haemorrhagic conjunctivitis occurred in south-east Asia during 1970 and 1971, and became epidemic in Lucknow in May 1971. From the conjunctival swabs adenovirus-like agents were isolated in monkey kidney tissue culture; one was typed as adenovirus 2. In paired sera rising antibody titres were found against an adeno-like agent isolated and the picornavirus (EC2/71) isolated in Singapore. The epidemics in south-east Asia were caused by a picornavirus while in Lucknow both adenovirus and picornavirus appeared to be implicated.

Acute Disease↗

PubMed2004

Multiple sclerosis attacks are associated with picornavirus infections.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system, which often follows a relapsing-remitting (RR) course with discrete attacks. MS attacks have been associated with upper respiratory infections (URIs), but the specific viruses responsible have not been identified. We studied a cohort of 16 RRMS patients experiencing URI and followed them for clinically identifiable attacks. The viral causes of 21 separate URIs were investigated using culture and polymerase chain reaction (PCR) of nasal swab specimens, and by serology. Sibleys 'at-risk' period for MS attacks, beginning two weeks before and continuing for five weeks after a URI, was used for the analysis. Seven of the nine (78%) URIs due to picornaviruses were associated with an MS attack during the at-risk period. By contrast, only two of 12 (17%) picornavirus-negative URIs were associated with an MS attack (P = 0.01). The possible role of picornaviruses in the pathogenesis of MS deserves further study.

Adult↗

PubMed1999

In vitro inhibitory effects of dual combinations of picornavirus replication inhibitors.

To assess the possible interactions among picornavirus replication inhibitors, inhibitory effects of dual combinations of enviroxime, disoxaril, arildone, S-7, guanidine, PTU-23, and HBB on poliovirus type 1 (Mahoney) replication in FL cells were tested. Beforehand, the 50% inhibitory concentration (IC50) in the plaque inhibition test was been determined for each individual compound, i.e. enviroxime-0.2 micromol/l, disoxaril-0.3 micromol/l, arildone-2.7 micromol/l, (S-7)-100 micromol/l, guanidine-200 micromol/l, (PTU-23)-200 micromol/l, and HBB-300 micromol/l. Each of the dual combinations, in which enviroxime or HBB was one of the partners, showed synergistic or additive effects. Combining disoxaril with enviroxime, HBB or PTU-23 resulted in synergism, while combining it with guanidine, S-7 or arildone led to antagonism. Arildone showed additive or synergistic effects when combined with enviroxime, HBB and PTU-23, and antagonistic ones when combined with disoxaril, S-7 or guanidine. All dual combinations of PTU-23 were synergistic with the exception of the pair of PTU-23 + guanidine that was antagonistic. Guanidine had additive to synergistic interactions with HBB or enviroxime but antagonistic ones with disoxaril, arildone and PTU-23. Guanidine or PTU-23 when combined with S-7 showed an unusual effect - synergistic one with an antagonistic zone. The combinations of S-7 with enviroxime or HBB were synergistic but those with disoxaril or arildone were antagonistic. Research on interactions of picornavirus replication inhibitors could possibly contribute to the development of efficient chemotherapy of infectious diseases caused by picornaviruses as well as to the better understanding of the mode of action of those inhibitors.

Antiviral Agents↗

PubMed2000

[The correlation between the exacerbation of bronchial asthma and picornavirus (human rhino virus) infection in throat gargles by RT-PCR].

Viral infection is one of important factors to cause the exacerbation of bronchial asthma. We have investigated 167 adults of asthmatics to clarify the correlation between viral infection and exacerbation of asthma. Patients were classified to four group by the symptoms of common cold and asthma attack. Furthermore, we have examined Picornavirus and Human rhino virus RNA from throat gargles of patients using RT-PCR (reverse transcription--polymerase chain reaction) method. Forty of 65 (61.5%) asthmatics with common cold revealed asthma attack and common cold was significantly associated with acute exacerbation of asthma (p < 0.01). We identified Picornavirus RNA, which include 113 of Human rhino virus serotypes and enterovirus, from the samples of 16 of 52 (30.8%) patients who had acute exacerbation. It was significantly higher than the detection rate of viral RNA from patient without asthma attack. Furthermore, we analyzed Human rhino virus RNA from the same samples by RT-PCR and 93.7% of Picornavirus were identified as Human rhino virus. Taken together, these findings suggest that common cold is significantly associated with the exacerbation of bronchial asthma. Human rhino virus infection might be one of important virus in this procedure.

Adult↗