Inhibition of interferon signaling by rabies virus phosphoprotein P:: Activation-dependent bindinig of STAT1 and STAT2
Inhibition of interferon signaling by rabies virus phosphoprotein P:: Activation-dependent bindinig of STAT1 and STAT2
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DOI：
10.1128/jvi.80.6.2675-2683.2006
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发表时间：
2006-03-01
影响因子：
5.4
通讯作者：
Conzelmann, KK
中科院分区：
文献类型：
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作者：
Brzózka, K;Finke, S;Conzelmann, KK
狂犬病毒（RV）磷蛋白P是一种干扰素（IFN）拮抗剂，可对抗1型干扰素的转录激活（K. 布若兹卡、S. 芬克和K. K. 康泽尔曼，《病毒学杂志》79：7673 - 7681，2005年）。我们在此表明，RV P还通过将活化的STATs滞留于细胞质中，阻止了RV感染细胞中IFN -α/β和IFN -γ刺激的JAK - STAT信号传导。在感染RV SAD L16的细胞中，或者在转染质粒表达RV P蛋白的细胞中，IFN刺激反应元件和γ激活序列控制的基因表达受到严重损害。相反，一种表达少量P的重组RV丧失了干扰JAK - STAT信号传导的能力。在表达RV P的细胞中，IFN介导的STAT1和STAT2的酪氨酸磷酸化未受损害；相反，细胞提取物中酪氨酸磷酸化的STATs明显积聚，这表明STAT循环存在缺陷。在P存在的情况下，活化的STAT1和STAT2无法在细胞核中积聚。值得注意的是，只有从先前用IFN -α或IFN -γ刺激过的细胞提取物中，STAT1和STAT2才能与RV P共沉淀，而在未受刺激的细胞中未观察到P与STATs的结合。RV P对酪氨酸磷酸化的STATs这种有条件的、依赖于IFN激活的结合对于一种病毒IFN拮抗剂来说是独特的。P的10个C末端残基是对抗JAK - STAT信号传导所必需的，但对于抑制IFN -β的转录激活则不是必需的，从而证明了RV P在对抗宿主IFN反应中具有两种独立的功能。
Rabies virus (RV) phosphoprotein P is an interferon (IFN) antagonist counteracting transcriptional activation of type 1 IFN (K. Brzozka, S. Finke, and K. K. Conzelmann, J. Virol 79:7673-7681, 2005). We here show that RV P in addition is responsible for preventing IFN-alpha/beta- and IFN-gamma-stimulated JAK-STAT signaling in RV-infected cells by the retention of activated STATs in the cytoplasm. Expression of IFN-stiniulated response element- and gamma-activated sequence-controlled genes was severely impaired in cells infected with RV SAD L16 or in cells expressing RV P protein from transfected plasmids. In contrast, a recombinant RV expressing small amounts of P had lost the ability to interfere with JAK-STAT signaling. IFN-mediated tyrosine phosphorylation of STAT1 and STAT2 was not impaired in RV P-expressing cells; rather, a defect in STAT recycling was suggested by distinct accumulation of tyrosine-phosphorylated STATs in cell extracts. In the presence of P, activated STAT1 and STAT2 were unable to accumulate in the nucleus. Notably, STAT1 and STAT2 were coprecipitated with RV P only from extracts of cells previously stimulated with IFN-alpha or IFN-gamma, whereas in nonstimulated cells no association of P with STATs was observed. This conditional, IFN activation-dependent binding of tyrosine-phosphorylated STATs by RV P is unique for a viral IFN antagonist. The 10 C-terminal residues of P are required for counteracting JAK-STAT signaling but not for inhibition of transcriptional activation of IFN-beta, thus demonstrating two independent functions of RV P in counteracting the host's IFN response.