OTUB1和OTUB2对细胞抗病毒信号转导的调控机制
摘要
细胞抗病毒天然免疫反应是细胞防御病毒感染产生的自我保护反应。细胞被病毒感染后,模式识别受体(pattern recognition receptor, PRR)识别病原相关分子模式(pathogen-associated molecular pattern, PAMP),启动Ⅰ型干扰素表达。Ⅰ型干扰素通过JAK-STAT信号通路诱导下游抗病毒基因表达,这些蛋白共同参与细胞抗病毒天然免疫。Ⅰ型干扰素的表达依赖多种转录因子的共同参与,其中IRF3 (interferon-regulatory factor 3)和NF-κB尤其重要。
识别病毒PAMP的PRR包括Toll样受体(Toll-like receptor, TLR)、RIG-I样受体(RIG-I-like receptor, RLR)和DNA受体。TLRs识别病毒组分后,通过MyD88依赖型信号通路或TRIF依赖型信号通路分别激活NF-κB和IRF3,进而诱导Ⅰ型干扰素表达。而RLRs则通过RNA结合结构域识别病毒dsRNA,利用级联激活和招募结构域(caspase activation and recruitment domain, CARD)结合下游接头蛋白VISA (virus-induced signaling adaptor) o VISA通过招募不同的蛋白形成VISA复合物分别激活NF-κB和IRF3。一方面,VISA利用TRAF结合结构域(TRAF interaction motifs)招募TRAF2 (tumor necrosis factor receptor 2)和TRAF6 (tumor necrosis factor receptor 6),然后TRAF2和TRAF6泛素化RIP1和NEMO/IKKy,激活IKK (inhibitor ofκB kinase)复合物和NF-κB信号通路；另一方面VISA结合TRAF3、MITA (mediator of IRF3 activator)、TBK1 (TRAF familymember-associated NF-κB activator-binding kinase 1),激活IRF3信号通路,NF-KB和IRF3结合到Ⅰ型干扰素基因启动子上,诱导Ⅰ型干扰素表达。
机体通过一系列的蛋白修饰调节细胞抗病毒免疫反应,其中,泛素化和去泛素化修饰是重要的调控手段。例如E3泛素链接酶TRIM25通过K63-连接的泛素链修饰RIG-Ⅰ,辅助RIG-Ⅰ招募VISA。因此,我们推测有未知蛋白通过泛素化或去泛素化作用参与病毒诱导的Ⅰ型干扰素信号通路。在本研究中,我们鉴定出两个去泛素化酶--OTUB1和OTUB2,负调控病毒诱导的Ⅰ型干扰素信号通路。过表达OTUB1和OTUB2抑制由病毒诱导的ISRE、NF-κB、IFNβ启动子的激活和IFNB1及其下游细胞因子RANTES的表达。与之相对应,通过siRNA技术减少内源性OTUB1和OTUB2的表达,不仅能有效地促进仙台病毒(sendai virus,SeV)诱导的IFNβ的表达,而且能显著抑制水泡口炎病毒(vesicle stomatitis virus, VSV)的复制。免疫共沉淀实验显示,OTUB1和OTUB2参与病毒诱导的Ⅰ型干扰素信号通路中非常重要的复合物——VISA复合物的形成。进一步的研究结果表明,OTUB1和OTUB2特异性去泛素化TRAF3和TRAF6。这些实验显示：OTUB1和OTUB2通过去泛素化TRAF3和TRAF6负调控病毒诱导的Ⅰ型干扰素信号通路。
Viral infection triggered a series of signaling events that lead to induction of typeⅠinterferons (IFNs). TypeⅠIFNs then activate the JAK-STAT signal transduction pathways, leading to transcriptional induction of a wide range of downstream antiviral genes and subsequent innate antiviral response. It has been shown that transcriptional activation of the IFNB1 gene requires coordinate and cooperative assembly of an enhanceosome that contains multiple transcription factors such as NF-κB and IRF3.
The innate immune system has developed at least two kinds of pathogen recognition receptor (PRRs) for the recognition of viral RNAs. One is mediated by membrane-bound Toll-like receptors (TLRs) such as TLR3. Engagement of TLR3 by dsRNA triggers TRIF (an adaptor of the TLR pathway)-mediated signaling pathway, thereby leading to IRF3 and NF-κB activation. The second one involves the cytosolic RIG-I-like receptor (RLR) family members RIG-Ⅰ, MDA5 and Lgp2. Upon viral infection, the RNA helicase domains of RIG-Ⅰand MDA5 serve as intracellular viral RNA receptors, whereas their CARD modules are associated with the downstream CARD-containing adapter protein VISA (also known as MAVS, IPS-1, and Cardif). Various studies have demonstrated that VISA plays a central role in assembling a complex that activates distinct signaling pathways leading to NF-κB and IRF3 activation respectively. VISA is associated with TRAF2 and TRAF6 through its TRAF interaction motifs. It has been shown that TRAF2 and TRAF6 facilitate K63-linked polyubiquitination of RIP and NEMO/IKKy respectively and these processes cause activation of IKKs and subsequent NF-κB. VISA is also associated with TRAF3, another member of the TRAF protein family. Gene knockout studies have demonstrated that TRAF3 is essential in virus-triggered IRF3 activation and typeⅠIFN induction.
Ubiquitination and deubiquitination have emerged as critical post-translational regulatory mechanisms for activation or attenuation of the virus-triggered IFN response pathways. It has been shown that the E3 ubiquitin ligase TRIM25 catalyzes K63-linked ubiquitination of RIG-Ⅰand this ubiquitination is essential for the interaction of RIG-Ⅰwith VISA as well as for its ability to signal. We speculate the unknown ubiquitinases and deubiquitinases involved in IFN-βproduction. In this study, we identified two deubiquitinases, OTUB1 and OTUB2, inhibited virus-triggered IFN induction. Overexpression of OTUB1 and OTUB2 inhibited SeV-induced activation of ISRE, NF-κB, IFN promoter and IFNB1 expression, whereas knockdown of OTUB1 and OTUB2 had opposite effects and inhibited vesicular stomatitis virus (VSV) replication. Coimmunoprecipitations indicate OTUB1 and OTUB2 are associated with the VISA-associated complex, the components in the virus-triggered IFN signaling. We further found that OTUB1 and OTUB2 regulate the antiviral responses by specifically deubiquitinating TRAF3 and TRAF6. These findings suggest that OTUB1 and OTUB2 negativly regulates virus-triggered signaling by their deubiquitinase activity.
识别病毒PAMP的PRR包括Toll样受体(Toll-like receptor, TLR)、RIG-I样受体(RIG-I-like receptor, RLR)和DNA受体。TLRs识别病毒组分后,通过MyD88依赖型信号通路或TRIF依赖型信号通路分别激活NF-κB和IRF3,进而诱导Ⅰ型干扰素表达。而RLRs则通过RNA结合结构域识别病毒dsRNA,利用级联激活和招募结构域(caspase activation and recruitment domain, CARD)结合下游接头蛋白VISA (virus-induced signaling adaptor) o VISA通过招募不同的蛋白形成VISA复合物分别激活NF-κB和IRF3。一方面,VISA利用TRAF结合结构域(TRAF interaction motifs)招募TRAF2 (tumor necrosis factor receptor 2)和TRAF6 (tumor necrosis factor receptor 6),然后TRAF2和TRAF6泛素化RIP1和NEMO/IKKy,激活IKK (inhibitor ofκB kinase)复合物和NF-κB信号通路；另一方面VISA结合TRAF3、MITA (mediator of IRF3 activator)、TBK1 (TRAF familymember-associated NF-κB activator-binding kinase 1),激活IRF3信号通路,NF-KB和IRF3结合到Ⅰ型干扰素基因启动子上,诱导Ⅰ型干扰素表达。
机体通过一系列的蛋白修饰调节细胞抗病毒免疫反应,其中,泛素化和去泛素化修饰是重要的调控手段。例如E3泛素链接酶TRIM25通过K63-连接的泛素链修饰RIG-Ⅰ,辅助RIG-Ⅰ招募VISA。因此,我们推测有未知蛋白通过泛素化或去泛素化作用参与病毒诱导的Ⅰ型干扰素信号通路。在本研究中,我们鉴定出两个去泛素化酶--OTUB1和OTUB2,负调控病毒诱导的Ⅰ型干扰素信号通路。过表达OTUB1和OTUB2抑制由病毒诱导的ISRE、NF-κB、IFNβ启动子的激活和IFNB1及其下游细胞因子RANTES的表达。与之相对应,通过siRNA技术减少内源性OTUB1和OTUB2的表达,不仅能有效地促进仙台病毒(sendai virus,SeV)诱导的IFNβ的表达,而且能显著抑制水泡口炎病毒(vesicle stomatitis virus, VSV)的复制。免疫共沉淀实验显示,OTUB1和OTUB2参与病毒诱导的Ⅰ型干扰素信号通路中非常重要的复合物——VISA复合物的形成。进一步的研究结果表明,OTUB1和OTUB2特异性去泛素化TRAF3和TRAF6。这些实验显示：OTUB1和OTUB2通过去泛素化TRAF3和TRAF6负调控病毒诱导的Ⅰ型干扰素信号通路。
Viral infection triggered a series of signaling events that lead to induction of typeⅠinterferons (IFNs). TypeⅠIFNs then activate the JAK-STAT signal transduction pathways, leading to transcriptional induction of a wide range of downstream antiviral genes and subsequent innate antiviral response. It has been shown that transcriptional activation of the IFNB1 gene requires coordinate and cooperative assembly of an enhanceosome that contains multiple transcription factors such as NF-κB and IRF3.
The innate immune system has developed at least two kinds of pathogen recognition receptor (PRRs) for the recognition of viral RNAs. One is mediated by membrane-bound Toll-like receptors (TLRs) such as TLR3. Engagement of TLR3 by dsRNA triggers TRIF (an adaptor of the TLR pathway)-mediated signaling pathway, thereby leading to IRF3 and NF-κB activation. The second one involves the cytosolic RIG-I-like receptor (RLR) family members RIG-Ⅰ, MDA5 and Lgp2. Upon viral infection, the RNA helicase domains of RIG-Ⅰand MDA5 serve as intracellular viral RNA receptors, whereas their CARD modules are associated with the downstream CARD-containing adapter protein VISA (also known as MAVS, IPS-1, and Cardif). Various studies have demonstrated that VISA plays a central role in assembling a complex that activates distinct signaling pathways leading to NF-κB and IRF3 activation respectively. VISA is associated with TRAF2 and TRAF6 through its TRAF interaction motifs. It has been shown that TRAF2 and TRAF6 facilitate K63-linked polyubiquitination of RIP and NEMO/IKKy respectively and these processes cause activation of IKKs and subsequent NF-κB. VISA is also associated with TRAF3, another member of the TRAF protein family. Gene knockout studies have demonstrated that TRAF3 is essential in virus-triggered IRF3 activation and typeⅠIFN induction.
Ubiquitination and deubiquitination have emerged as critical post-translational regulatory mechanisms for activation or attenuation of the virus-triggered IFN response pathways. It has been shown that the E3 ubiquitin ligase TRIM25 catalyzes K63-linked ubiquitination of RIG-Ⅰand this ubiquitination is essential for the interaction of RIG-Ⅰwith VISA as well as for its ability to signal. We speculate the unknown ubiquitinases and deubiquitinases involved in IFN-βproduction. In this study, we identified two deubiquitinases, OTUB1 and OTUB2, inhibited virus-triggered IFN induction. Overexpression of OTUB1 and OTUB2 inhibited SeV-induced activation of ISRE, NF-κB, IFN promoter and IFNB1 expression, whereas knockdown of OTUB1 and OTUB2 had opposite effects and inhibited vesicular stomatitis virus (VSV) replication. Coimmunoprecipitations indicate OTUB1 and OTUB2 are associated with the VISA-associated complex, the components in the virus-triggered IFN signaling. We further found that OTUB1 and OTUB2 regulate the antiviral responses by specifically deubiquitinating TRAF3 and TRAF6. These findings suggest that OTUB1 and OTUB2 negativly regulates virus-triggered signaling by their deubiquitinase activity.
引文
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