Signal regulatory protein α negatively regulates both TLR3 and cytoplasmic pathways in type I interferon induction
Signal regulatory protein α negatively regulates both TLR3 and cytoplasmic pathways in type I interferon induction
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DOI：
10.1016/j.molimm.2008.03.012
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发表时间：
2008-06-01
影响因子：
3.6
通讯作者：
Wang, Hong-Yang
中科院分区：
文献类型：
--
作者：
Dong, Li-Wei;Kong, Xiao-Ni;Wang, Hong-Yang
双链RNA(DsRNA)的识别激活了干扰素调节因子3(IRF3)依赖的抗病毒因子的表达。先天免疫系统通过两条不同的途径识别病毒dsRNA。首先，Toll样受体3(TLR3)检测内体中吞噬的dsRNA。此外，解旋酶维甲酸诱导蛋白I(RIG-I)/黑色素瘤分化相关基因5(MDA5)与病毒复制过程中产生的胞质dsRNA结合。RIG-I/MDA5和TLR3都可以结合病毒dsRNA的合成类似物多核苷：多核胞苷酸(Poly(I：C))，并介导I型干扰素的产生。在这里，我们表明信号调节蛋白(SIRP)a负调控TLR3和RIG-1/MDA5依赖的抗病毒途径。通过RNA干扰抑制SIRPα的表达，导致Poly(I：C)治疗后IRF3和MAPK通路的激活增强，同时上调了干扰素-β和干扰素-β诱导的基因转录激活。磷脂酰肌醇3-激酶(PI3K)活性对dsRNA诱导干扰素-β和干扰素-β诱导基因表达的要求被观察到PI3K抑制剂不能激活干扰素-β和干扰素-β诱导基因的表达。PI3K的活性对IRF3的激活是必不可少的，它在Poly(I：C)刺激下被招募到SIRPα的磷酸化酪氨酸残基上，导致下游激酶AKT的活性降低。因此，SIRPα在I型干扰素诱导中可能部分地通过与信号转导PI3K的结合和隔离来完成其抑制功能。(C)2008爱思唯尔有限公司。保留所有权利。
Recognition of double-stranded RNA (dsRNA) activates interferon-regulatory factor 3 (IRF3)-dependent expression of anti-viral factors. The innate immune system recognizes viral dsRNA through two distinct pathways. First, the Toll-like receptor 3 (TLR3) detects dsRNA phagocytosed in endosomes. In addition, the helicases retinoic acid induced protein I (RIG-I)/melanoma differentiation associated gene 5 (MDA5) binds cytoplasmic dsRNA generated during viral replication. Both RIG-I/MDA5 and TLR3 can bind polyriboinosinic:polyribocytidylic acid (poly(I:C)), the synthetic analog of viral dsRNA, and mediate type I IFN production. Here we show that signal regulatory protein (SIRP) a negatively regulates both TLR3- and RIG-1/MDA5-dependent anti-viral pathways. Suppression of SIRP alpha expression by RNA interference results in enhanced activation of IRF3 and MAPK pathways after poly(I:C) treatment, coupled with the up-regulation of IFN-beta and IFN-beta-inducible gene transcriptional activation. The requirement of phosphoinositide 3-kinase (PI3K) activity for the induction of IFN-beta and IFN-beta-inducible genes by dsRNA is supported by the observation that a PI3K inhibitor failed to activate IFN-beta and IFN-beta-inducible gene expression. PI3K, whose activity is essential for activation of IRF3, is recruited to the phosphorylated tyrosine residues of SIRP alpha upon poly(I:C) stimulation, which lead to a reduction in the activity of the downstream kinase AKT. Thus SIRP alpha may accomplish its inhibitory function in type I IFN induction, in part, through its association and sequestration of the signal transducer PI3K. (C) 2008 Elsevier Ltd. All rights reserved.