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Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717, USA
Correspondence
Michele E. Hardy
mhardy{at}montana.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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A table showing primers used in this study is available as supplementary material in JGV Online.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). These viruses belong to the family Reoviridae, with genomes composed of 11 segments of double-stranded RNA (dsRNA). Six structural proteins, VP1–VP4, VP6 and VP7, encapsidate the dsRNA to assemble infectious triple-layered particles (TLPs). The genome also encodes six non-structural proteins, NSP1–NSP6, shown to function in transcription, dsRNA replication, translation of viral mRNA, cellular pathology and virus particle maturation (Estes, 2001).
Recent data have assigned one role for non-structural protein NSP1 in evasion of the innate immune response to rotavirus infection. NSP1 binds the cellular transcription factor interferon regulatory factor 3 (IRF3) (Graff et al., 2002) and targets it for degradation by the proteasome early post-infection (Barro & Patton, 2005). IRF3 resides latent in the cytoplasm and is activated in response to virus infection (Au et al., 1995). IRF3 is phosphorylated by kinases TBK1/IKK
; it then dimerizes and translocates to the nucleus, where it assembles in coordination with additional transcription co-factors on interferon (IFN) and IFN-stimulated gene (ISG) promoters (Fitzgerald et al., 2003; Hiscott et al., 2003; Wathelet et al., 1998). IRF3 is required for induction of IFN
; thus interference with its function effectively downregulates antiviral gene expression. Downregulation of IFN expression through inhibition of IRF3 function has been reported for viruses within several families. The mechanisms of IRF3 antagonism vary and include inhibition of phosphorylation (Basler et al., 2003; Brzozka et al., 2005; Foy et al., 2003), nuclear translocation (Talon et al., 2000) and inhibition of transcription complex assembly (Jennings et al., 2005; Juang et al., 1998). Rotavirus NSP1 is the only viral protein shown thus far to inhibit IRF3 activation by a mechanism involving early proteasome targeting.
Modification of eukaryotic proteins with ubiquitin (Ub) prior to proteasome degradation requires an E1 activating enzyme, E2 conjugating enzyme, and an E3 ligase that interacts with both the E2 and the target substrate to mediate the transfer of Ub from the E2 to the target substrate (Pickart, 2001). E3 ligases fall into two major classes of proteins that contain either a catalytic HECT domain or a RING domain (Jackson et al., 2000). HECT domains have homology to E6-AP, with strict conservation of a cysteine residue approximately 35 amino acids from the C terminus that transiently interacts with Ub. RING-finger domains, in contrast, are cysteine–histidine-rich adaptor domains that facilitate transfer of Ub from E2 to the substrate protein. Typical RING domains in cellular proteins consist of cysteine and histidine residues spaced in a C3HC4 pattern that coordinates two zinc ions in a cross-brace motif (Barlow et al., 1994). However, evidence continues to accumulate that variations of the C3HC4 pattern exist in the RING superfamily and are present in both viral and cellular proteins with E3 ligase activity (Aravind et al., 2003).
Several viral proteins with cysteine–histidine-rich zinc-binding domains have demonstrated E3 ligase activity, and many of the cellular targets of viral E3s are associated with regulation of immune responses to infection. For example, V proteins of viruses in the family Paramyxoviridae target the signal transducers and activators of transcription (STATs) for proteasome degradation and consequently downregulate type I IFN responses (Horvath, 2004). The Kaposi's sarcoma herpesvirus (KSHV) RTA protein targets IRF7 to the proteasome (Yu et al., 2005) and the KSHV K3 proteins MIR1 and MIR2 downregulate major histocompatibility complex class I expression (Coscoy et al., 2001). Herpes simplex virus (HSV) ICP0 is known to induce, either directly or indirectly, proteasome-dependent degradation of the stress-related kinase DNA-PK and promyelocytic leukaemia protein PML, among others (Hagglund & Roizman, 2004). Each of these proteins has intrinsic E3 ligase activity, but only ICP0 has a typical RING-domain signature.
NSP1 is the least conserved protein encoded by the rotavirus genome, but an N-terminal zinc-binding motif is completely conserved (Mitchell & Both, 1990). This domain is not necessary for virus replication because rotavirus strains that encode a truncated NSP1 that lacks the zinc-finger motif replicate in cell culture, although plaque sizes are smaller than those of wild-type counterparts (Taniguchi et al., 1996). We have shown that the zinc-binding domain is important, but not sufficient, for interaction with IRF3 (Graff et al., 2002). The presence of this domain and the finding that NSP1 targets IRF3 for proteasome degradation suggest that NSP1 may have E3 Ub ligase activity.
To increase understanding of the mechanisms by which NSP1 modulates the function of IRF3, we investigated the role of the zinc-binding domain in NSP1-mediated IRF3 binding and degradation. Expression of NSP1 of bovine rotavirus strain B641 in transfected cells resulted in IRF3 degradation, and mutation of conserved cysteine and histidine residues abolished this activity. In addition, two residues in the zinc-binding domain, as well as another highly conserved histidine residue outside the zinc-binding domain, were associated with differential stability of NSP1. Together, the data illustrate the importance of the zinc-binding domain of NSP1 in interference with the function of IRF3 and suggest that NSP1 may have E3 ligase activity associated with an atypical RING domain. We further discovered that IRF3 was activated and stable in cells infected with porcine rotavirus strain OSU. OSU NSP1 has an intact zinc-binding domain and showed a weak interaction with IRF3. Disruption of the zinc-binding domain of OSU NSP1 resulted in increased stability, similar to B641 NSP1. The data derived from experiments with OSU NSP1 suggest the existence of rotavirus strains with the inability to downregulate IFN responses by targeting IRF3 and raise the possibility of alternative targets of NSP1 in antiviral signalling pathways.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Isolation, characterization and propagation of rotavirus strains B641 (bovine), A5-16 (bovine), OSU (porcine) and SA11-4F (simian) have been described (Pereira et al., 1984; Taniguchi et al., 1996; Theil et al., 1977; Woode et al., 1983). Rotavirus TLPs were concentrated by centrifugation for 2 h at 26 000 r.p.m. in an SW28 rotor at 4 °C, and then banded on a 3.09 M CsCl gradient prepared in TNC buffer (10 mM Tris pH 7.5, 100 mM NaCl, 5 mM CaCl2). Infectious TLPs were collected and concentrated by centrifugation for 2 h at 35 000 r.p.m. in an SW55 rotor. The TLPs were suspended in M199 lacking FBS and stored at –80 °C. Virus titres were determined by plaque assay.
Immunoblotting.
Protein samples were separated on SDS-polyacrylamide gels. After transfer to nitrocellulose, membranes were blocked in 10 % milk (w/v) in PBS (10 % BLOTTO). Membranes were incubated overnight at room temperature with indicated primary antibody diluted in 0.5 % BLOTTO. Membranes were rinsed three times with 0.5 % BLOTTO, and then incubated for 2 h at room temperature with peroxidase-conjugated secondary antibodies (Jackson ImmunoResearch). Proteins were detected with ECL (Pierce). Primary antibodies include anti-GFP (BD, 1 : 500), anti-IRF3 (Active Motif, 1 : 3000), anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Ambion, 1 : 2000) and anti-c-myc (BD, 1 : 2000).
IRF3 analysis in virus-infected cells.
MA104 cells were infected at the indicated m.o.i. with rotavirus strains that were activated with 10 µg trypsin ml–1 for 30 min at 37 °C. Whole-cell extracts were prepared by scraping the cells into radioimmunoprecipitation (RIPA) buffer containing 150 mM NaCl, 1 % sodium deoxycholate, 1 % Triton X-100, 0.1 % SDS, 10 mM Tris–HCl pH 7.2. IRF3 levels were determined by immunoblot as described above.
Plasmids.
Plasmid construction was performed using standard cloning techniques. Site-directed mutagenesis reactions were carried out using a QuikChange XL kit (Stratagene). Supplementary Table S1 (available in JGV Online) lists the primers used in these experiments. B641 NSP1 (primers 1 and 2) and OSU NSP1 (primers 3 and 4) were cloned into pGBKT7 (BD Clontech). To generate a bicistronic construct encoding EYFP and NSP1, the poliovirus internal ribosome entry sequence (IRES) was amplified (primers 5 and 6) from pNLink (kindly provided by R. Lloyd, Baylor College of Medicine, Houston, TX, USA) and cloned into pEYFP-C1 (BD Clontech) to generate pEYFP-IRES. pB-NSP1 and pO-NSP1 were constructed by amplifying myc-tagged B641 NSP1 (primers 7 and 8) and myc-tagged OSU NSP1 (primers 7 and 9) from the pGBKT7 constructs described above followed by insertion into pEYFP-IRES downstream of the IRES motif.
For site-directed mutagenesis, the primers listed in supplementary table S1 and their corresponding reverse complement sequences were utilized. A panel of single amino acid substitutions in B641 NSP1 was generated with primers 10–12 for changing residues C54, H79 and H136, respectively. Primer 13 was used to construct a mutation at residue C54 in OSU NSP1.
Transfections.
293 cells were cultured to approximately 90 % confluence in 12-well plates or 60 mm dishes and transfected with indicated plasmids using TransIT 293 transfection reagent (Mirus) according to the manufacturer's specifications. Whole-cell extracts were harvested at 48 h post-transfection by scraping into RIPA buffer. Transfection efficiencies were determined by fluorescence microscopy or by GFP immunoblots. Proteasome inhibitor MG132 (Calbiochem) was included in the medium at a concentration of 100 µM where indicated.
GST pull-down assay.
GST pull-down assays were performed as described previously (Daughenbaugh et al., 2003). GST and GST–IRF324–422 (Graff et al., 2002) were induced with 1 mM IPTG for 4 h at 37 °C. Bacteria were pelleted by centrifugation and suspended in buffer composed of 50 mM Tris pH 8.0, 2 mM EDTA and 1 % Triton X-100. The bacteria were lysed by sonication with 10 s pulses. Soluble fusion proteins were collected from the supernatant following a 10 min centrifugation at 12 000 g. GST and GST–IRF3 were purified with glutathione–Sepharose 4B beads (GE Healthcare).
Transfected 293 cells were rinsed once with PBS and detached from the plastic by treatment with 0.5x trypsin–EDTA. The cells were transferred to 1.5 ml microcentrifuge tubes and pelleted for 5 min at 500 g. Cells were lysed in 200 µl lysis buffer composed of 50 mM Tris pH 7.5, 15 mM NaCl, 140 mM KCl, 2 % NP-40, and the volume was increased by addition of 500 µl wash buffer (20 mM Tris, pH 7.5, 15 mM NaCl, 140 mM KCl, 0.1 % NP-40).
For pull-down assays, 300 µl transfected cell lysate was incubated with 200 µl GST or GST–IRF3 bound to glutathione–Sepharose 4B beads and this mixture was incubated for 2 h at 4 °C with end-over-end rotation. The beads were pelleted for 5 min at 500 g and then washed three times with 500 µl wash buffer. Proteins were eluted with 10 mM reduced glutathione and analysed by SDS-PAGE, followed by Coomassie staining or immunoblot. Images of the immunoblots were obtained on an Image Station 2000MM (Kodak). The ratio of NSP1 bound by GST–IRF3 to the input level of NSP1 was calculated by densitometric analysis using 1D Image Analysis software v3.6 (Kodak).
In vitro transcription–translation.
OSU NSP1 wild-type and OSU NSP1 C54A RNA were transcribed from pGBKT7-OSU NSP1 and pGBKT7-OSU NSP1 C54A plasmids and then translated for 90 min at 30 °C in the presence of 0.4 µCi (14.8 kBq) Trans 35S label µl–1 (MP Biomedicals) in the TNT T7 Coupled Reticulocyte Lysate system (Promega). Reactions included 100 µM MG132 or an equivalent amount of DMSO as a vehicle control.
Pulse–chase analysis.
Wild-type and mutant B641 NSP1 proteins were translated in cell-free extracts for 90 min at 30 °C in 25 µl reactions in the presence of 0.4 µCi (14.8 kBq) Trans 35S label µl–1. Reactions were chased by adding unlabelled methionine and cysteine to a final concentration of 1 mM each. Samples (5 µl) were collected from the reactions at 0, 30, 60 and 120 min post-chase and mixed with SDS-PAGE loading buffer. NSP1 was visualized by SDS-PAGE and autoradiography, and expression levels were quantified by densitometry.
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RESULTS |
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). These data are consistent with those reported for cells infected with simian strain SA11-4F (Barro & Patton, 2005). A5-16 is a bovine rotavirus variant with a rearrangement in gene segment 5 that encodes an NSP1 truncated at 40 aa (Taniguchi et al., 1996). In contrast to B641-infected cells, IRF3 was activated and stable when cells were infected with A5-16. These results were expected given the lack of a full-length NSP1 encoded in the A5-16 genome. An unexpected result was the observation that IRF3 was activated and stable over the course of infection with porcine strain OSU. Gene 5 of OSU was cloned and sequenced; there is 100 % amino acid identity between NSP1 of our laboratory strain and that in the published database (GenBank accession no. U08432
[GenBank]
). These data demonstrate the existence of NSP1 variants that have contrasting phenotypes with respect to targeting IRF3 for proteasome degradation.
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). We evaluated OSU NSP1 expression by metabolic labelling of cells infected at an m.o.i. of 20 and, although B641 NSP1 and SA11-4F NSP1 were detectable, OSU NSP1 could not be unequivocally discerned from the background of cell proteins (data not shown). These results suggested that the level of OSU NSP1 could be a limiting factor in effects on IRF3.
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). The status of IRF3 was measured in transfected cells by immunoblot and, as observed in OSU-infected cells, IRF3 was stable, whereas IRF3 was degraded in the presence of B641 NSP1 (Fig. 2c). Together these data show that OSU NSP1 is not able to direct proteasome-dependent degradation of IRF3 in human or monkey cell lines.
Comparative analysis of B641 NSP1 and OSU NSP1 interactions with IRF3
The observation that OSU NSP1 expression could not induce degradation of IRF3 suggested that these two proteins may not interact. The interaction between B641 NSP1 and IRF3 was discovered in a yeast two-hybrid screen. We first tested for a potential interaction between OSU NSP1 and IRF3 in yeast, and no interaction was observed (data not shown). To test for possible interaction in an alternative system, GST pull-down assays were performed with GST–IRF323–422 and pB-NSP1- or pO-NSP1-transfected cell lysates. Despite the difference in NSP1 levels (Fig. 3a), significantly more B641 NSP1 bound GST–IRF3 than did OSU NSP1 (Fig. 3b, top panel). The same amount of GST–IRF3 was eluted from each reaction (Fig. 3b, bottom panel). Binding was quantified by determining the ratio of NSP1 bound to GST–IRF3 to the input levels of NSP1. OSU NSP1 bound IRF3 at a detectable level, but the binding was <10 % of that observed for B641 NSP1 (Fig. 3c). These data suggest that the stability of IRF3 in OSU-infected cells and in OSU NSP1-transfected cells is due to the lack of a stable interaction with IRF3 in human or monkey cell lines.
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). Each mutant was tested for the ability to bind IRF3 by pull-down assay and to cause IRF3 degradation in transfected cells. 293 cells were transfected with pEYFP-IRES, pB-NSP1 (wild-type) or pB-NSP1 mutants containing single amino acid substitutions C54A, H79L or H136L. Each mutation reduced the B641 NSP1–IRF3 interaction compared to the wild-type protein (Fig. 4b, c). The H136L mutant retained the highest level of IRF3 binding at approximately 30 %.
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). The significant increase in the amount of mutant protein compared to wild-type protein suggests that NSP1 may regulate its own stability via a functional zinc-binding domain, in addition to regulating the stability of IRF3. Pulse–chase analysis of wild-type and mutant NSP1 confirmed that the mutations resulted in increased stability (Fig. 5). The H136L mutation is outside the zinc-binding domain. This mutant retained the ability to direct IRF3 degradation but, interestingly, was more stable than wild-type NSP1. The explanation for this result is not entirely clear, but the data suggest that IRF3 degradation and intrinsic NSP1 stability are functionally separable.
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).
B641 NSP1 and OSU NSP1 are susceptible to proteasome degradation in transfected cells
Higher levels of OSU NSP1 compared to B641 NSP1 were consistently observed in transfected cells. We confirmed by sequencing that the OSU NSP1- and B641 NSP1-expressing constructs were exactly the same, with the only difference being in the protein-coding regions. One explanation for the level of OSU NSP1 was that, in contrast to B641 NSP1, OSU NSP1 may not be susceptible to rapid proteasome degradation. This possibility was tested by measuring NSP1 levels in cells transfected in the presence of proteasome inhibitor MG132. The data shown in Fig. 6 indicate an approximately 2.5-fold increase in the amount of both OSU and B641 NSP1 in the presence of MG132. These data demonstrate an inherent sensitivity of NSP1 to proteasome degradation and show that the high level of OSU NSP1 in transfected cells is not due to insensitivity to proteasome degradation.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). B641 NSP1 bound IRF3 strongly and IRF3 was degraded in a proteasome-dependent manner, whereas the OSU NSP1–IRF3 interaction was weak and IRF3 was stable. Second, the RING domain is important for the activity of an E3. There is clearly strong evolutionary pressure to maintain the cysteine and histidine residues that form the zinc-binding domain in NSP1, because these residues are completely conserved in all published NSP1 sequences. Mutation of two conserved cysteine and histidine residues of the B641 NSP1 zinc-binding domain significantly weakened the NSP1–IRF3 interaction, and IRF3 was not degraded in the presence of these mutants. A mutation to a highly conserved histidine residue downstream of the zinc-binding domain was less detrimental to the strength of the NSP1–IRF3 interaction and did not abrogate the ability of B641 NSP1 to cause IRF3 degradation. The spacing of the conserved cysteine and histidine residues in NSP1 does not correspond to the RING consensus found in cellular E3 ligases. Thus the NSP1 zinc-binding domain probably represents a viral protein with a variant E3 signature, as noted previously for KSHV RTA and paramyxovirus V proteins (Horvath, 2004; Yu et al., 2005). Finally, E3 proteins are commonly capable of autoregulation through self-ubiquitination (Joazeiro & Weissman, 2000). Mutations within the RING or RING-like domains, or inhibition of proteasome activity, cause accumulation of E3 proteins in cells (Yang et al., 2000; Yu et al., 2005). Inhibition of proteasome activity resulted in accumulation of both B641 NSP1 and OSU NSP1 in transfected cells, and mutations within the zinc-binding motif of either strain caused NSP1 to accumulate in transfected cells or cell-free extracts. Collectively, the observations described above are consistent with the hypothesis that NSP1 is an E3 ubiquitin ligase.
NSP1–IRF3 binding experiments showed that OSU NSP1 could bind IRF3, but at levels lower than 10 % of those observed with B641 NSP1. These data were not a result of insufficient protein because OSU NSP1 accumulated to higher levels than B641 NSP1 in transfected cells. A weak interaction suggests that there are sequence or structural variations in OSU NSP1 that result in assembly of an unstable proteasome-targeting complex. It should be noted, however, that experiments were performed in cells of monkey or human origin. Thus the possibility exists that there is species specificity or co-factors involved in OSU NSP1 interactions that are not required for the bovine NSP1 interactions with human or monkey IRF3. Sequence comparisons between B641 NSP1 and OSU NSP1 did not reveal obvious differences in the N-terminal domain of the protein that would suggest a basis for distinct IRF3-binding patterns. The highest sequence variation among NSP1 of all rotavirus strains is in the C-terminal half of the protein (Mitchell & Both, 1990). Previous data showed that the C terminus of NSP1 played a role in IRF3 binding and IRF3 degradation in infected cells (Barro & Patton, 2005; Graff et al., 2002). Consistent with this, a C-terminal fragment of OSU NSP1 did not interact with IRF3 in a yeast two-hybrid assay (data not shown). These data suggest that the C terminus is critical for interactions with IRF3, and that variations in the C termini of NSP1 of B641 and OSU may direct potentially different target specificities.
IRF3 targeting by B641 NSP1, but not by OSU NSP1, leads to the prediction that OSU NSP1 may target a unique set of substrates. Precedents for this prediction come from studies of the paramyxovirus V proteins. V proteins from different paramyxoviruses target distinct proteins involved in JAK/STAT signal transduction. For example, Simian virus 5 targets STAT1 for proteasome degradation (Didcock et al., 1999), while Human parainfluenza virus 2 targets STAT2 (Parisien et al., 2001) and mumps virus V protein can target both STAT1 and STAT3 (Nishio et al., 2002). Additional support for the prediction that B641 NSP1 and OSU NSP1 have unique substrates is the dichotomy in the stability of each of these proteins when comparing protein levels in cells. In 293 cells, OSU NSP1 is more stable than B641 NSP1. KSHV RTA accumulates in cells until its IRF7 substrate is no longer detectable, at which point RTA also becomes undetectable, presumably through autoregulation (Yu et al., 2005). Based on this, we predict that 293 cells have a higher cumulative level of OSU NSP1-specific substrate than B641 NSP1 substrate, resulting in higher levels of OSU NSP1 accumulation. Alternatively, as an example, HSV ICP0 is protected from self-ubiquitination in cells through interactions with ubiquitin-specific protease USP7 (Canning et al., 2004), and such an inhibitory interaction also may exist for OSU NSP1. The variations in reported NSP1 levels of different rotavirus strains could be a function of the cumulative specific substrate levels or interacting proteins in different cell lines for each unique NSP1, in addition to levels regulated by their individual translation efficiencies (Patton et al., 2001). Expression of OSU NSP1 fails to cause IRF3 degradation in 293 cells, and it will be worthwhile to investigate whether OSU NSP1 targets other protein(s) involved in the induction of an IFN response. OSU NSP1 targeting of other signalling molecules involved in IFN induction or amplification could have a similar biological effect to B641 NSP1 targeting IFN induction by degrading IRF3.
Generation of rotavirus strains deficient in the ability of NSP1 to interfere with IFN signal transduction would be an attractive feature in an attenuated rotavirus vaccine. The effects of IFN production in stimulating innate immune responses have been well documented, but only recently have the effects of IFN production on adaptive immune responses been appreciated (Pulendran & Ahmed, 2006). Biochemical analysis of the phenotype of rotavirus NSP1 mutants such as those provided here will help provide a framework for rational attenuated vaccine development.
Note: While this manuscript was under review, Pina-Vasquez et al. (2007) reported regulation of NSP1 levels by proteasome sensitivity, confirming data reported here.
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ACKNOWLEDGEMENTS |
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Received 31 May 2006;
accepted 24 October 2006.
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