p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons
p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons
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DOI：
10.1093/emboj/18.20.5601
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发表时间：
1999-10-15
期刊：
影响因子：
11.4
通讯作者：
Williams, BRG
中科院分区：
文献类型：
--
作者：
Goh, KC;Haque, SJ;Williams, BRG
胞浆磷脂酶A(2)(CPLA(2))的激活是干扰素-α反应形成转录因子复合干扰素刺激基因因子3(ISGF3)的先决条件，我们在这里证明了p38丝裂原激活蛋白激酶(MAPK)是CPLA(2)的激活剂，对干扰素-α和干扰素-γ信号转导都是必不可少的。P38的特异性抑制剂SB203580可抑制ISGF3的形成，但对信号转导和转录激活因子(STAT)1同源二聚体的形成无明显影响。尽管如此，干扰素-α和干扰素-γ的抗病毒活性均被SB203580减弱，任一种干扰素处理均导致p38的快速和瞬时激活，两种IFN均可诱导STAT1 Ser727的磷酸化，该磷酸化可被SB203580抑制，但不被细胞外信号相关激酶(ERK)1/2抑制剂(PD98059)抑制，显性阴性p38的表达导致STAT1丝氨酸磷酸化缺陷，并减弱干扰素-γ介导的抗病毒杀伤作用。由ISGF3或STAT1同源二聚体介导的报告活性被SB203580抑制，而被p38上游激活剂MKK6的结构活性突变体增强，因此，p38在两种IFN诱导的STAT1丝氨酸磷酸化和转录变化中起关键作用。
Activation of cytosolic phospholipase A(2) (cPLA(2)) is a prerequisite for the formation of the transcription factor complex interferon-stimulated gene factor 3 (ISGF3) in response to interferon-alpha (IFN-alpha), Here we show that p38 mitogen-activated protein kinase (MAPK), an activator of cPLA(2), is essential for both IFN-alpha and IFN-gamma signalling. SB203580, a specific inhibitor of p38, was found to inhibit ISGF3 formation but had no apparent effects on signal transducer and activator of transcription (STAT) 1 homodimer formation. Regardless of this, the antiviral activities of both IFN-alpha and IFN-gamma were attenuated by SB203580, Treatment with either IFN Led to rapid and transient activation of p38, Both IFNs induced STAT1 Ser727 phosphorylation, which was inhibited by SB203580 but not by an extracellular signal related kinase (ERK)1/2 inhibitor (PD98059), In an inducible 3T3-L1 clone, expression of dominant-negative p38 led to defective STAT1 serine phosphorylation and diminished IFN-gamma-mediated protection against viral killing. Reporter activity mediated by ISGF3 or STAT1 homodimer was diminished by SB203580 and enhanced by a constitutively active mutant of MKK6, the upstream activator of p38, Therefore, p38 plays a key role in the serine phosphorylation of STAT1 and transcriptional changes induced by both IFNs.