Phosphorylation of p38 MAPK and its downstream targets in SARS coronavirus-infected cells

Mizutani, Tetsuya; Fukushi, Shuetsu; Saijo, Masayuki; Kurane, Ichiro; Morikawa, Shigeru

doi:10.1016/j.bbrc.2004.05.107

Cited by 150 publications

(213 citation statements)

References 34 publications

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“…Whilst the upstream events that induce a conformational change in Bax are still unclear, recent studies suggest that caspase activation, Bid association and p38 MAPK initiate changes in Bax conformation, followed by its mitochondrial translocation (Desagher et al, 1999;Ghatan et al, 2000). In SARS-CoV-infected cells, there is increased activation of p38 MAPK and phosphorylation of its downstream targets (Mizutani et al, 2004). Here, we showed that the SARS-CoV 3a protein activates p38 MAPK.…”

Section: Discussionmentioning

confidence: 61%

Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Padhan

Minakshi

Towheed

et al. 2008

Journal of General Virology

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The molecular mechanisms governing severe acute respiratory syndrome coronavirus-induced pathology are not fully understood. Virus infection and some individual viral proteins, including the 3a protein, induce apoptosis. However, the cellular targets leading to 3a protein-mediated apoptosis have not been fully characterized. This study showed that the 3a protein modulates the mitochondrial death pathway in two possible ways. Activation of caspase-8 through extrinsic signal(s) caused Bid activation. In the intrinsic pathway, there was activation of caspase-9 and cytochrome c release from the mitochondria. This was the result of increased Bax oligomerization and higher levels of p53 in 3a protein-expressing cells, which depended on the activation of p38 MAP kinase (MAPK) in these cells. For p38 activation and apoptosis induction, the 3a cytoplasmic domain was sufficient. In direct Annexin V staining assays, the 3a protein-expressing cells showed increased apoptosis that was attenuated with the p38 MAPK inhibitor SB203580. A block in nuclear translocation of the STAT3 transcription factor in cells expressing the 3a protein was also observed. These results have been used to present a model of 3a-mediated apoptosis. INTRODUCTIONThe aetiological agent for severe acute respiratory syndrome (SARS) was identified as a novel coronavirus (SARS-CoV) (Peiris et al., 2003). SARS-CoV has a polyadenylated, positive-sense RNA genome of approximately 30 kb (Marra et al., 2003). In addition to the prototypic coronavirus genes, the SARS-CoV genome also contains nine unique open reading frames (ORFs) (Marra et al., 2003). Of these, orf3a is the largest and encodes a protein of 274 aa, variously called ORF3A (Ito et al., 2005), X1 (Rota et al., 2003) or U274 (Tan et al., 2004b). The 3a protein has been predicted to contain an N-terminal signal peptide followed by three transmembrane domains and a C-terminal cytoplasmic domain of approximately 150 aa (Zeng et al., 2004).The 3a protein is associated with virus particles produced following infection of Vero E6 or Caco-2 cells (Ito et al., 2005;Shen et al., 2005) and can assemble into virus-like particles when co-expressed with the membrane and envelope proteins in insect cells (Shen et al., 2005). In vitro studies have also shown the 3a protein to interact with the viral envelope, membrane and spike proteins (Tan et al., 2004b;Tan, 2005) and the cellular protein caveolin-1 (Padhan et al., 2007). A deletion of orf3a was shown to reduce virus titres, but not to eliminate virus replication (Yount et al., 2005), and convalescent sera from SARS patients have antibodies to the 3a protein (Tan et al., 2004a), suggesting that it is expressed during virus infection of the host. The 3a protein was shown to upregulate the expression of fibrinogen in A549 lung epithelial cells and to possess an ionchannel activity selective for monovalent cations (Lu et al., 2006). Ectopic expression of the 3a protein has been shown to induce apoptosis in Vero E6 cells through activation of caspase-8, chromatin c...

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Section: Discussionmentioning

confidence: 61%

Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Padhan

Minakshi

Towheed

et al. 2008

Journal of General Virology

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“…Virus infection and dsRNA have been shown to activate MAPK pathways in different cell types via PKR-dependent and -independent mechanisms and MAPK activation has been implicated in the regulation of inflammatory gene expression (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). We have shown that dsRNA-and EMCV infection stimulates ERK activation and ERK-dependent regulation of IL-1 expression (19, 29 -31).…”

Section: Role Of Mapk In the Regulationmentioning

confidence: 99%

Role of MAPK in the Regulation of Double-Stranded RNA- and Encephalomyocarditis Virus-Induced Cyclooxygenase-2 Expression by Macrophages

Steer

Moran

Christmann

et al. 2006

The Journal of Immunology

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In response to virus infection or treatment with dsRNA, macrophages express the inducible form of cyclooxygenase-2 (COX-2) and produce proinflammatory prostaglandins. Recently, we have shown that NF-κB is required for encephalomyocarditis virus (EMCV)- and dsRNA-stimulated COX-2 expression in mouse macrophages. The dsRNA-dependent protein kinase R is not required for EMCV-stimulated COX-2 expression, suggesting the presence of protein kinase R-independent pathways in the regulation of this antiviral gene. In this study, the role of MAPK in the regulation of macrophage expression of cyclooxygenase-2 (COX)-2 in response to EMCV infection was examined. Treatment of mouse macrophages or RAW-264.7 cells with dsRNA or infection with EMCV stimulates the rapid activation of the MAPKs p38, JNK, and ERK. Inhibition of p38 and JNK activity results in attenuation while ERK inhibition does not modulate dsRNA- and EMCV-induced COX-2 expression and PGE2 production by macrophages. JNK and p38 appear to selectively regulate COX-2 expression, as inhibition of either kinase fails to prevent dsRNA- or EMCV-stimulated inducible NO synthase expression by macrophages. Using macrophages isolated from TLR3-deficient mice, we show that p38 and JNK activation and COX-2 expression in response to EMCV or poly(IC) does not require the presence the dsRNA receptor TLR3. These findings support a role for p38 and JNK in the selective regulation of COX-2 expression by macrophages in response to virus infection.

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“…MAPKAPK2 has been shown to stimulate muscle contractility via (P)-hsp27 (Ibitayo et al, 1999), which also appears to be activated in γSG -/-tissue but not in C57 tissue. Because (P)-MAPKAPK2 is a target for (P)-ERK and is itself stretch-activated (Ibitayo et al, 1999;Krook et al, 2000;Mizutani et al, 2004;Ryder et al, 2000), these proteins may be part of a hypercontractile signaling loop (Fig. 7) that couples to externally imposed (stretch) as well as internally generated mechanical stress (prestress).…”

Section: Signaling Possibilities For γSgmentioning

confidence: 99%

“…P38 MAPK is known to be stretch-and stressactivated (Azuma et al, 2001;Martineau and Gardiner, 2001;Mizutani et al, 2004), and increased phosphorylation of p38 MAPK has been linked to increased apoptosis (Deschesnes et al, 2001). Thus, although we found that p38 MAPK exhibits decreased activation in unstretched γSG -/-tissue (Table 2), the 900% increase of p38 MAPK phosphorylation in stretched γSG -/-tissue (compared with a 500% increase in stretched normal cells) (Table 3) reveals its sensitivity to mechanotransduction.…”

Section: Signaling Possibilities For γSgmentioning

confidence: 99%

γ-Sarcoglycan deficiency increases cell contractility, apoptosis and MAPK pathway activation but does not affect adhesion

Griffin

Feng

Tewari

et al. 2005

Journal of Cell Science

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The functions of γ-sarcoglycan (γSG) in normal myotubes are largely unknown, however γSG is known to assemble into a key membrane complex with dystroglycan and its deficiency is one known cause of limb-girdle muscular dystrophy. Previous findings of apoptosis from γSG-deficient mice are extended here to cell culture where apoptosis is seen to increase more than tenfold in γSG-deficient myotubes compared with normal cells. The deficient myotubes also exhibit an increased contractile prestress that results in greater shortening and widening when the cells are either lightly detached or self-detached. However, micropipette-forced peeling of single myotubes revealed no significant difference in cell adhesion. Consistent with a more contractile phenotype, acto-myosin striations were more prominent in γSG-deficient myotubes than in normal cells. An initial phosphoscreen of more than 12 signaling proteins revealed a number of differences between normal and γSG–/– muscle, both before and after stretching. MAPK-pathway proteins displayed the largest changes in activation, although significant phosphorylation also appeared for other proteins linked to hypertension. We conclude that γSG normally moderates contractile prestress in skeletal muscle, and we propose a role for γSG in membrane-based signaling of the effects of prestress and sarcomerogenesis.

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Phosphorylation of p38 MAPK and its downstream targets in SARS coronavirus-infected cells

Cited by 150 publications

References 34 publications

Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Role of MAPK in the Regulation of Double-Stranded RNA- and Encephalomyocarditis Virus-Induced Cyclooxygenase-2 Expression by Macrophages

γ-Sarcoglycan deficiency increases cell contractility, apoptosis and MAPK pathway activation but does not affect adhesion

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