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. 2004 Nov 5;577(1-2):187-92.
doi: 10.1016/j.febslet.2004.10.005.

Tyrosine dephosphorylation of STAT3 in SARS coronavirus-infected Vero E6 cells

Tetsuya Mizutani  1 , Shuetsu Fukushi, Masaaki Murakami, Toshio Hirano, Masayuki Saijo, Ichiro Kurane, Shigeru Morikawa
Affiliations

Tyrosine dephosphorylation of STAT3 in SARS coronavirus-infected Vero E6 cells

Tetsuya Mizutani et al. FEBS Lett. .

Abstract

Severe acute respiratory syndrome (SARS) has become a global public health emergency. p38 mitogen-activated protein kinase (MAPK) and its downstream targets are activated in SARS coronavirus (SARS-CoV)-infected Vero E6 cells and activation of p38 MAPK enhances the cytopathic effects of SARS-CoV infection. In addition, weak activation of Akt cannot prevent SARS-CoV infection-induced apoptosis in Vero E6 cells. In the present study, we demonstrated that signal transducer and activator of transcription (STAT) 3, which is constitutively phosphorylated at tyrosine (Tyr)-705 and slightly phosphorylated at serine (Ser)-727 in Vero E6 cells, was dephosphorylated at Tyr-705 on SARS-CoV infection. In addition to phosphorylation of p38 MAPK in virus-infected cells, other MAPKs, i.e., extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK), were phosphorylated. Although inhibitors of ERK1/2 and JNK (PD98059 and SP600125) had no effect on phosphorylation status of STAT3, inhibitors of p38 MAPK (SB203580 and SB202190) partially inhibited dephosphorylation of STAT3 at Tyr-705. Tyr-705-phosphorylated STAT3 was localized mainly in the nucleus in mock infected cells, whereas STAT3 disappeared from the nucleus in virus-infected cells. As STAT3 acts as an activator of transcription in the nucleus, these results suggest that STAT3 lacks its activity on transcription in SARS-CoV-infected Vero E6 cells.

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Figures

Figure 1
Figure 1
Infection of Vero E6 cells with SARS‐CoV affected the signaling pathway of STAT3. Western blotting analysis of proteins from SARS‐CoV‐infected Vero E6 cells was performed using antibodies that recognized forms of STAT3 phosphorylated at Tyr‐705 or Ser‐727.
Figure 2
Figure 2
Phosphorylation levels of upstream kinases of STAT3 in virus‐infected cells. Western blotting analyses were performed using anti‐phospho JAK1, JAK2, and Tyk2 antibodies.
Figure 3
Figure 3
Subcellular localization of Tyr‐phosphorylated STAT3. (A) Vero E6 cells were incubated in DMEM containing 0%, 2% or 5% FCS for 18 h. After subcellular fractionation, Western blotting was performed using anti‐phospho STAT3 (Tyr) antibody. (B) C, M, N, S, and T indicate cytosolic, organelle/membrane, nuclear, cytoskeletal, and total cellular fraction, respectively.
Figure 4
Figure 4
IL‐22 induces Tyr phosphorylation of STAT3. (A) Vero E6 cells were treated with IL‐22 from 0 to 90 min. Cellular proteins were sampled every 15 min. Western blotting was performed using anti‐phospho STAT3 (Tyr and Ser) antibodies. (B) SARS‐CoV‐infected Vero E6 cells were treated with IL‐22 for 20 min at 18 h.p.i., and then, Western blot analysis was performed using anti‐phospho STAT3 (Tyr) and anti‐phospho p38 MAPK.
Figure 5
Figure 5
MAPKs phosphorylation in virus‐infected cells. Western blotting analysis of proteins from SARS‐CoV‐infected Vero E6 cells was performed using anti‐phospho ERK1/2, JNK, MEK1/2, MKK4, MKK7, and MKK3/6 antibodies.
Figure 6
Figure 6
Effects of treatment of SARS‐CoV‐infected Vero E6 cells with p38 MAPK inhibitor. (A) Vero E6 cells were infected with SARS‐CoV at m.o.i. of 10, and then incubated with SB203580, PD98059, and SP600125 at concentrations from 10 to 50 μM for 17 h. Western blotting analyses were performed to detect Tyr‐705‐ and Ser‐727‐phosphorylated forms of STAT3. (B) SB202190 was used as a p38 MAPK inhibitor.
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