Respiratory syncytial virus induces RelA release from cytoplasmic 100-kDa NF-κB2 complexes via a novel retinoic acid-inducible gene-I•NF-κB-inducing kinase signaling pathway
Respiratory syncytial virus induces RelA release from cytoplasmic 100-kDa NF-κB2 complexes via a novel retinoic acid-inducible gene-I•NF-κB-inducing kinase signaling pathway
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DOI：
10.1074/jbc.m802729200
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发表时间：
2008-08-22
影响因子：
4.8
通讯作者：
Brasier, Allan R.
中科院分区：
文献类型：
--
作者：
Liu, Ping;Li, Kui;Brasier, Allan R.
呼吸道合胞病毒(RSV)是世界范围内儿童严重下呼吸道感染的主要原因。呼吸道合胞病毒感染呼吸道上皮细胞，通过核因子-kappa B途径激活炎症基因。核因子-kappa B受两条途径控制，一条正则途径从I kappa Bα抑制剂释放隔离的relA复合体，第二条非正则途径从100 kDa的NF-kappa B2复合体释放RelB。最近，我们发现维甲酸诱导基因I(RIG-I)是典型途径上游的一个主要的细胞内RSV感受器。在本研究中，我们意外地发现RIG-I沉默也抑制了P100对52 kDa核因子-kappaB2(“P52”)的处理，这表明RIG-I在功能上位于由(NIKK)-I-.α亚基组成的非规范调节激酶复合体的上游。免疫共沉淀实验不仅证实了Nik与RIG-I及其下游接头线粒体抗病毒信号转导(MAVS)有关，而且还证实了IKKα与MAVS之间的关联。为了进一步了解(NIKK)-I-.α途径的作用，我们用野生型、IKK-γ(-/-)、NIK(-/-)和IKKα(-/-)缺陷的MEF细胞比较了RSV诱导的NF-kappa B激活。有趣的是，我们发现在典型通路缺陷的IKK伽马(-/-)细胞中，RSV通过从P100复合体中释放而诱导RELA。RSV仍能激活IKKγ(-/-)细胞中IP10、RANTES和Groβ基因的表达，这种诱导可被小干扰RNA介导的relA基因敲除而不是RelB沉默所抑制。这些数据表明，响应RSV感染的部分relA激活是由RIG-I(.)MAV下游的非规范(NIKK)-I-α复合体参与的“串扰”途径诱导的。该途径可能成为RSV治疗的潜在靶点。
Respiratory syncytial virus (RSV) is a primary cause of severe lower respiratory tract infection in children world wide. RSV infects airway epithelial cells, where it activates inflammatory genes via the NF-kappa B pathway. NF-kappa B is controlled by two pathways, a canonical pathway that releases sequestered RelA complexes from the I kappa B alpha inhibitor, and a second, the noncanonical pathway, that releases RelB from the 100-kDa NF-kappa B2 complex. Recently we found that the retinoic acid-inducible gene I (RIG-I) is a major intracellular RSV sensor upstream of the canonical pathway. In this study, we surprisingly found that RIG-I silencing also inhibited p100 processing to 52-kDa NF-kappa B2 ("p52"), suggesting that RIG-I was functionally upstream of the noncanonical regulatory kinase complex composed of (NIKIKK)-I-.alpha subunits. Co-immunoprecipitation experiments not only demonstrated that NIK associated with RIG-I and its downstream adaptor, mitochondrial antiviral signaling (MAVS), but also showed the association between IKK alpha and MAVS. To further understand the role of the (NIKIKK)-I-.alpha pathway, we compared RSV-induced NF-kappa B activation using wild type, Ikk gamma(-/-), Nik(-/-), and Ikk alpha(-/-)-deficient MEF cells. Interestingly, we found that in canonical pathway-defective Ikk gamma(-/-) cells, RSV induced RelA by liberation from p100 complexes. RSV was still able to activate IP10, Rantes, and Gro beta gene expression in Ikk gamma(-/-) cells, and this induction was inhibited by small interfering RNA-mediated RelA knockdown but not RelB silencing. These data suggest that part of the RelA activation in response to RSV infection was induced by a "cross-talk" pathway involving the noncanonical (NIKIKK)-I-.alpha complex downstream of RIG-I(.)MAVS. This pathway may be a potential target for RSV treatment.