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Short Communication |
1 Department of Cell and Molecular Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Beutenbergstrasse 11a, D-07745 Jena, Germany
2 Institute of Virology and Antiviral Therapy, Medical Center, Friedrich Schiller University, Hans-Knoell-Strasse 2, D-07745 Jena, Germany
3 Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany
4 Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute Beutenbergstrasse 11a, D-07745 Jena, Germany
Correspondence
Thomas Munder
thomas.munder{at}hki-jena.de
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ABSTRACT |
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A supplementary table showing the differentially regulated or modified proteins detected upon CVB3 infection of human HeLa and HepG2 cells is available in JGV Online.
Present address: MEDLAB Gotha-Laborpraxis Bösenberg, Schützenberg 10, D-99867 Gotha, Germany. 
Present address: CLONDIAG Chip Technologies GmbH, Löbstedter Straße 103-105, D-07749 Jena, Germany.
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MAIN TEXT |
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TOPABSTRACTMAIN TEXTREFERENCES |
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; Reyes & Lerner, 1985; Woodruff, 1980). CVB3 may cause cardiac arrhythmias and acute heart failure; chronic forms of this disease may occur, leading to dilated cardiomyopathy (DCM) (Frisk et al., 1984; Kandolf, 1998; Kandolf & Hofschneider, 1989). DCM results in a progressive heart insufficiency and a significantly increased death rate (Gillum, 1986; Sugrue et al., 1992). The pathogenesis of coxsackievirus infection has been studied extensively in different murine models, demonstrating that the outcome of this viral infection is determined by complex interactions among several variables of the virus and the host (Chow et al., 1991; Huber, 1997). In addition, the mechanisms for how CVB3 causes myocarditis are not very well characterized (Bowles & Towbin, 1998).
The host elements responsible for the changes observed during the course of CVB3-mediated myocarditis have not yet been determined intensively. It is well documented that the picornavirus proteases 2A and 3C cleave cellular proteins, e.g. the translation initiation factor eIF4G (Haghighat et al., 1996) or the poly(A)-binding protein (Kerekatte et al., 1999), resulting in a host translation shut-off. However, not much is known about cellular proteins that are modified during the infection process and which are necessary furthermore for the virus to replicate. Previously, we demonstrated a direct interaction between the CVB3 capsid protein VP2 and the human protein Siva, overexpressed upon a CVB3 infection (Henke et al., 2000, 2001), which is involved in the CD27/CD70-transduced apoptotic pathway (Prasad et al., 1997). To expand rapidly the portrait of host gene expression involved in the pathogenesis of viral myocarditis and particularly to examine the expression of proteins, we used a proteome-wide approach. Proteins of infected and non-infected HeLa cells as well as HepG2 cells were separated on two-dimensional (2D) gels and spots were analysed by peptide mass fingerprinting in combination with time of flight (TOF)/TOF-mass spectrometry (MS) sequence analysis.
Viruses were propagated in cells at 37 °C under 5 % CO2 atmosphere, using Dulbecco's modified Eagle's medium for HeLa and RPMI 1640 for HepG2 cells supplemented with 10 % fetal bovine serum. Typically, subconfluent (90–95 % confluence) cell monolayers were infected with CVB3 at an m.o.i. of 5. The cell lines were obtained from the German Collection of Microorganisms and Cell Cultures GmbH (DSMZ, Braunschweig, Germany) and cultivated according to the manufacturer's instructions. Control cells were mock infected. The cells were harvested after visual inspection of the onset of the cytopathic effect, characterized by shrinking of the cells and subsequent disintegration of the cellular assembly (Wessely et al., 1998a, b). HeLa cells were harvested 6 h after infection with CVB3 and HepG2 cells at 12 h after infection. Cells taken after shorter infection periods (3 h for HeLa cells and 6 h for HepG2 cells) showed only marginal differences in their protein composition (not shown). The 2D separation and identification of proteins is described in the legend of Fig. 1.
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shows all proteins that were found in at least two independent experiments. Some proteins were detected exclusively in either HeLa or HepG2 cells, but the majority of them were found in both cell lines. Thus, we conclude that an infection of different cell types with CVB3 results in similar responses independent of the cellular background.
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). The hypothesis is supported further by the fact that we identified several differentially regulated heterogeneous nuclear ribonucleoproteins, which are necessary for ribosome assembly (Table 1
). Also very promising was our finding that the poly(A)-binding proteins 1 and 4 were either modified or downregulated in CVB3-infected cells, which may be due to the degradation of these proteins by viral proteases (Kerekatte et al., 1999).
There is increasing evidence that a CVB3 infection leads to a loss of the cytoskeleton integrity (Badorff et al., 1999; Bonneau et al., 1985; Joachims & Etchison, 1992). We found that several proteins including the housekeeping gene products actin, lamin and various subunits of tubulin (see Table 1) associated with cell structure were differentially regulated upon CVB3 infection. The high molecular mass forms of 
-actin were shifted during the infection process to lower molecular mass isoforms or degraded pieces thereof. In Fig. 1, all numbered spots refer to -actin as shown by MS analysis. The different isoelectric points and molecular masses could be explained by a varying degree of post-translational modifications or by degradation. Proteins 1 and 3 were found at higher concentrations in non-infected cells than in infected cells. This was in contrast to spots 4, 5, 6 and 7 that were found to be more abundant in infected cells. The lower molecular mass of the latter protein spots could be explained by degradation of -actin in CVB3-infected cells. Similarly as shown in Fig. 2(a) and (b) both lamin, i.e. spot 1a, and nucleophosmin, i.e. spot 2a, shifted to spot 1b and spot 2b, respectively, after infection due to post-translational modifications, thus explaining potential differential alteration of functions.
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; Hozak et al., 1995). Lamins A, C and B2 are present in the adult heart (Manilal et al., 1999). Their critical role in maintaining the structural integrity of the nuclear lamina and the spatial organization of proteins in the inner nuclear membrane is well documented. Interactions with lamins are also required for correct positioning of nuclear pore complexes and for anchoring heterochromatin at the nuclear periphery. Although the role of intranuclear lamins has not been clearly defined, the lamin scaffolding may contribute to the internal stability of the nuclear matrix. Collectively, these functions implicate lamins as important determinants of nuclear architecture (Burke & Stewart, 2002; Hutchison, 2002; Stuurman et al., 1998). The discovery of mutations in the lamin A gene has highlighted a previously unsuspected role for nuclear lamina proteins in the pathogenesis of a variety of human muscle diseases, including DCM in combination with conduction system disease (Fatkin et al., 1999). The mechanisms by which lamin A gene mutations cause diverse tissue-specific phenotypes have not been elucidated. It is tempting to speculate that lamin and/or other proteins of the cytoskeleton are directly or indirectly affected by a CVB3 infection, which subsequently may result in one cellular basis for myocarditis. Nevertheless, it has to be considered that degradation of lamin is a marker for apoptotic events (Herzog et al., 2004), and that CVB3 infection induces apoptosis (Henke et al., 2000). Therefore, we cannot discriminate as to whether degradation of lamin is a direct effect of a viral protease or a secondary effect due to viral effected apoptosis.
Nucleophosmin is a nucleolar phosphoprotein involved in disparate functions, including nuclear transport, cellular proliferation and ribosome biogenesis (Borer et al., 1989; Herrera et al., 1996). This protein shows a shift horizontally to a lower pH in the 2D pattern in response to viral infection (Fig. 2b). This may be due to post-translational phosphorylation, because nucleophosmin is a nucleolar phosphoprotein (Okuwaki et al., 2001). It is known that nucleophosmin has the ability to shuttle between nucleus and cytoplasm (Borer et al., 1989) and binds to proteins presenting a nuclear localization signal (NLS), thus promoting their nuclear import (Szebeni et al., 1995). It forms a specific complex with the nucleolar protein p120 (Valdez et al., 1994), nucleolin (Li et al., 1996) and several viral proteins such as the Rev and Tat proteins of Human immunodeficiency virus (Fankhauser et al., 1991; Li, 1997). It has been reported that the 3BCD precursor of the Encephalomyocarditis virus (EMCV) localized to nuclei through an interaction with nucleophosmin (Aminev et al., 2003). We found the potential NLS K(K/R)X(K/R) (Chelsky et al., 1989) within the three-dimensional polymerase region of the CVB3 genome polyprotein (aa 1856–1859 by sequence analysis), which is conserved amongst all coxsackievirus variants. It has been suggested previously that nuclear targeting of viral proteases may be responsible for regulating cellular mRNA transcription via a proteolytic mechanism (Aminev et al., 2003). Interestingly, by comparing the protein sequences of the CVB3 strain Nancy to Woodruff (Woodruff, 1980) a substitution from lysine (K) to arginine (R) at the fourth position of the NLS is obvious, which does not change the consensus sequence. It is tempting to speculate that this region may contribute to the pathogenicity of the viruses.
An example of strongly upregulated proteins is the RNA-binding protein UNR, which was found to be overexpressed in CVB3-infected cells (Fig. 2c). UNR stimulates translation directed by the human rhinovirus and human poliovirus internal ribosomal entry site (IRES) in vitro (Boussadia et al., 2003). Translation of picornavirus RNAs is mediated by IRES elements and requires both standard eukaryotic translation initiation factors (eIF) and IRES-specific cellular transacting factors (ITAF). IRES is a cis-regulatory RNA element of about 450 nt. It folds into complex and highly conserved secondary structures and facilitates translation by direct binding of ribosomes to an internal site of the viral RNA. IRES elements have been found in various viral RNA and also in cellular mRNA (Belsham & Jackson, 2000; Hellen & Sarnow, 2001). In contrast to that, the IRES elements of EMCV and Foot-and-mouth-disease virus (FMDV) are not UNR-dependent. Thus, UNR is a specific regulator of rhinovirus and poliovirus translation and may represent a cell-specific determinant limiting replication of these viruses (Okuwaki et al., 2001). Another cellular ITAF specific for picornaviral IRES elements is the poly(rC)-binding protein (PCBP) (Blyn et al., 1997; Gamarnik & Andino, 1997; Walter et al., 1999). PCBP was also found to be regulated during a CVB3 infection. Interestingly, functional assays in vitro revealed that some picornavirus IRES elements require a specific combination of two or three of these ITAFs for an efficient translational activity. FMDV IRES-dependent translation needs a combination of the polypyrimidine tract-binding protein (PTB) and ITAF45, a cell-cycle-dependent protein homologous to the murine proliferation-associated protein (Pilipenko et al., 2000), whereas the poliovirus and the human rhinovirus IRES require PTB, PCBP and UNR for an effective translation (Boussadia et al., 2003; Hunt et al., 1999; Hunt & Jackson, 1999). An attractive hypothesis is that specific translation initiation factors assembled on IRES elements regulate translation initiation in the same way as specific transcription factors bound to promoters regulating transcription (Sachs & Buratowski, 1997). Therefore, besides the surface receptors required for infectivity, the different ITAFs participate in the pathogenicity process as well (Gromeier et al., 1996). Based on these data, we postulate that UNR and PCBP are relevant for efficient initiation of translation from the IRES of CVB3. We would like to stress that mRNA analysis does not elucidate regulation at this level. Only the technique of proteome analysis allows us to detect the definitive protein expression and regulation.
Recently it was shown that phosphorylation of the mitogen-activated protein (MAP) kinase p38 was increased during active replication of CVB3 (Kim et al., 2004; Si et al., 2005). We found that the cells respond to the CVB3 infection stress by modification of p38 kinase isoforms. This was detected using a specific antibody against all phosphorylated isoforms of this kinase (Fig. 2d). The protein reacts to environmental stress, pro-inflammatory cytokines and lipopolysaccharides by phosphorylating a number of transcription factors, such as ELK1 and ATF2 and several downstream kinases. Additionally, the MAP kinase p38 plays a critical role in the production of some cytokines, e.g. interleukin 6 (Pearson et al., 2001; Waetzig et al., 2002). It is known that CVB3 infection induces the expression of the tumour necrosis factor (TNF) receptor/ligand superfamily in heart (Seko et al., 1999). CD27, a member of the TNF-receptor superfamily, mediates its activity via the proapototic protein Siva (Prasad et al., 1997), which is upregulated during a CVB3 infection (Henke et al., 2000). The MAP kinase p38 is also a member of the TNF-signalling pathway (Pearson et al., 2001). Therefore, phosphorylation and activation of isoforms of the MAP kinase p38 is very likely a result of the infection, because of the activation of the TNF pathway. The occurrence of different phosphorylated isoforms allows the conclusion that p38 MAP kinase-dependent pathways are activated due to a CVB3-infection.
Interestingly, the expression of another enzyme, the fatty acid synthase, is regulated by a p38 stress MAP kinase-dependent mechanism (Li et al., 2004). The fatty acid synthase was found to be upregulated during the infection (Table 1). It has already been reported that fatty acid synthesis plays a role in replication of several viruses, e.g. Poliovirus (Fogg et al., 2003).
Taken together, our results demonstrate that striking changes in the protein composition between CVB3-infected cells and non-infected control cells occurred. Different pathways were influenced by the virus, including stress, cell signalling and gene expression machinery. The proteins give hints about the cellular responses upon CVB3 infection and provide possible mechanisms for the molecular basis of CVB3-induced diseases. Thus, our work contributes to the future research on pathogenicity processes and to the development of antiviral therapies.
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ACKNOWLEDGEMENTS |
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Received 6 January 2006;
accepted 24 April 2006.
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