E3泛素连接酶TRIM4和TRIM21调节细胞抗病毒天然免疫信号转导的机制
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摘要
细胞抗病毒天然免疫反应是细胞抵御病毒感染的第一道防线。病毒感染细胞以后,细胞内模式识别受体(pattern recognition receptors, PRRs)通过识别病原相关分子模式(pathogen-associated molecular patterns, PAMPs)激活下游信号通路,诱导Ⅰ型干扰素和炎症细胞因子的表达,从而启动整个天然免疫应答。
病毒在感染与复制的过程中,病毒的许多保守组分,比如病毒的dsRNA,会被细胞的PRRs如RIG-Ⅰ样受体(RIG-I like receptors, RLRs)识别。RLRs在识别病毒dsRNA以后,招募其下游接头蛋白VISA。 VISA—方面通过与TRAF3, MITA(?)(?)TBK1结合形成复合物,从而激活转录因子IRF3;另一方面,VISA通过对TRAF2/6的招募驱动IKK复合物激活另一个转录因子NF-κB。活化后的IRF3和NF-κB进入细胞核,共同作用启动Ⅰ型干扰素的表达。
蛋白修饰在机体调控细胞抗病毒天然免疫反应过程中起着十分重要的作用,泛素化与去泛素化修饰是多种蛋白修饰中较为重要的调控方式。为了寻找新的参与调控细胞抗病毒天然免疫反应的蛋白,我们通过报告基因实验筛选了352个泛素相关单克隆文库,我们发现,E3泛素连接酶TRIM4在过量表达的情况下能有效的激活NF-κB、ISRE和IFNβ启动子,并在仙台病毒刺激下协同仙台病毒诱导Ⅰ型干扰素的表达。通过shRNA干扰技术下调内源性的TRIM4表达能抑制病毒感染诱导的Ⅰ型干扰素产生。在免疫共沉淀的实验中,TRIM4(?)能够与RIG-Ⅰ病毒感染依赖性的相互作用。进一步的研究表明,TRIM4能够促进RIG-Ⅰ K63链接的泛素化,从而促进RIG-Ⅰ介导的Ⅰ型干扰素的产生。从我们的研究中产生了一些新的问题,例如TRIM25是一个能够介导RIG-I K63链接泛素化的E3泛素连接酶,那么TRMI4是否能够与TRIM25相关联而发挥其作用呢。此外,我们还将构建TRIM4基因敲除小鼠来验证我们的结论。
另一个TRIM蛋白家族成员TRIM21被报道在IRF3介导的信号通路中发挥着重要作用。然而,两个独立的研究组却得到了完全相反的结论。Yang研究组发现TRIM21(?)能通过与Pinl的相互作用增力(?)IRF3的稳定性,从而增加其对Ⅰ型干扰素的诱导。而在Higgs研究组研究中,TRIM21通过驱动IRF3的泛素化和降解来抑制Ⅰ型干扰素的产生。因此,我们构建了TRIM21基因敲除小鼠,希望能更直接的揭示TRIM21在抗病毒信号通路中的作用。我们的研究发现,TRIM21缺陷小鼠胚胎成纤维细胞相对于野生型细胞在仙台病毒感染下会产生更多的IFN-(3及其RANTES。我们的研究证明,生理情况下TRIM21能够抑制病毒诱导Ⅰ型干扰素的产生。而其中具体的分子机制还有待我们进一步的研究。而且之后对TRIM21缺陷型小鼠的全面表型分析将给我们提供更多的信息。
Antiviral immunity is the front line of host defence upon viral infection. The pattern recognition receptors (PRRs) activate downstream signaling in virus infection through pathogen-associated molecular patterns (PAMPs), and induce the production of type I interferons (IFNs) and proinfiammatory cytokines, which then cause the activation of innate immunity response.
In the infection and replication of virus, various viral components such as dsRNA can be recongnized by PRRs such as RIG-Ⅰ like receptors (RLRs). RLRs recognize the viral dsRNA, and then recruit a central adapter protein, designated virus-induced signaling adapter (VISA, also known as IPS-1, MAVS and CARDIF), which signals to different pathways. VISA associates with TRAF3, MITA and TBK1to activate IRF3by phosphorylation while VISA contemporarily interacts with TRAF2/TRAF6to activate IKK complex, leading to subsequent activation of another transcription factor, NF-κB. Activated IRF3and NF-κB translocate in nuclear and collaboratively trigger the expression of type ⅠIFN genes.
The regulation mechanism of host antiviral response is mediated by the modifications of cellular proteins, the major of which are ubiquitination and deubiquitination. To identify some new proteins which are involved in the regulation of cellular antiviral signaling through ubiquitination and deubiquitination, we chose pGL3-NF-κB as a reporter gene for screening a gene library. We found that transiently transfection of an E3ubiquitin ligase, TRIM4led to the significant activation of the NF-κB, ISRE, and IFNβ reporters, and increased the induction of type I interferons in SeV infection. Consistently, knockdown of endogenous TRIM4remarkably inhibited the production of SeV-induced type I interferons. Endogenous coimmunoprecipitation experiments also indicated that TRIM4associated with RIG-I, and the interaction of them was increased by the induction of viral infection. Further study showed that TRIM4collaboratively triggered the production of IFNs by the associating with RIG-Ⅰ and subsequently catalyzing the K63-linked ubiquitination of RIG-I. There are some new questions from our study, such as whether TRIM25, which was identified as an E3ubiquitin ligase which target RIG-Ⅰ for K63-linked ubiquitination of RIG-Ⅰ, could associate with TRIM4. Moreover, knockout mice of TRIM4should be generated to support our conclusion.
Another TRIM family member, TRIM21was identified playing a role as a regulator of IRF3signaling. However, two independent groups received the opposite conclusions. Yang et al demonstrated that TRIM21increases the stability of IRF3to enhance type I interferons induction by interaction with Pinl, a negative regulator of antiviral responses that mediates the ubiquitination and degradation of IRF3during virus infection. In contrast, Higgs et al found that TRIM21interacts with IRF3and promotes the ubiquitination and degradation of IRF3to limit IFNβ induction. Thus, to reveal the function of TRIM21in antiviral pathway, we generated TRIM21deficient mice. In our study, the embryonic fibroblast cells derived from TRIM21deficient mice showed increased production of IFNP and downstream gene RANTES in SeV infection. Our study confirmed that TRIM21in vivo inhibits in virus-induced production of type I IFNs, and the physiological molecular mechanism needs our further study. And comprehensive phenotype analysis of TRIM21deficient mice could furnish more information to us.
病毒在感染与复制的过程中,病毒的许多保守组分,比如病毒的dsRNA,会被细胞的PRRs如RIG-Ⅰ样受体(RIG-I like receptors, RLRs)识别。RLRs在识别病毒dsRNA以后,招募其下游接头蛋白VISA。 VISA—方面通过与TRAF3, MITA(?)(?)TBK1结合形成复合物,从而激活转录因子IRF3;另一方面,VISA通过对TRAF2/6的招募驱动IKK复合物激活另一个转录因子NF-κB。活化后的IRF3和NF-κB进入细胞核,共同作用启动Ⅰ型干扰素的表达。
蛋白修饰在机体调控细胞抗病毒天然免疫反应过程中起着十分重要的作用,泛素化与去泛素化修饰是多种蛋白修饰中较为重要的调控方式。为了寻找新的参与调控细胞抗病毒天然免疫反应的蛋白,我们通过报告基因实验筛选了352个泛素相关单克隆文库,我们发现,E3泛素连接酶TRIM4在过量表达的情况下能有效的激活NF-κB、ISRE和IFNβ启动子,并在仙台病毒刺激下协同仙台病毒诱导Ⅰ型干扰素的表达。通过shRNA干扰技术下调内源性的TRIM4表达能抑制病毒感染诱导的Ⅰ型干扰素产生。在免疫共沉淀的实验中,TRIM4(?)能够与RIG-Ⅰ病毒感染依赖性的相互作用。进一步的研究表明,TRIM4能够促进RIG-Ⅰ K63链接的泛素化,从而促进RIG-Ⅰ介导的Ⅰ型干扰素的产生。从我们的研究中产生了一些新的问题,例如TRIM25是一个能够介导RIG-I K63链接泛素化的E3泛素连接酶,那么TRMI4是否能够与TRIM25相关联而发挥其作用呢。此外,我们还将构建TRIM4基因敲除小鼠来验证我们的结论。
另一个TRIM蛋白家族成员TRIM21被报道在IRF3介导的信号通路中发挥着重要作用。然而,两个独立的研究组却得到了完全相反的结论。Yang研究组发现TRIM21(?)能通过与Pinl的相互作用增力(?)IRF3的稳定性,从而增加其对Ⅰ型干扰素的诱导。而在Higgs研究组研究中,TRIM21通过驱动IRF3的泛素化和降解来抑制Ⅰ型干扰素的产生。因此,我们构建了TRIM21基因敲除小鼠,希望能更直接的揭示TRIM21在抗病毒信号通路中的作用。我们的研究发现,TRIM21缺陷小鼠胚胎成纤维细胞相对于野生型细胞在仙台病毒感染下会产生更多的IFN-(3及其RANTES。我们的研究证明,生理情况下TRIM21能够抑制病毒诱导Ⅰ型干扰素的产生。而其中具体的分子机制还有待我们进一步的研究。而且之后对TRIM21缺陷型小鼠的全面表型分析将给我们提供更多的信息。
Antiviral immunity is the front line of host defence upon viral infection. The pattern recognition receptors (PRRs) activate downstream signaling in virus infection through pathogen-associated molecular patterns (PAMPs), and induce the production of type I interferons (IFNs) and proinfiammatory cytokines, which then cause the activation of innate immunity response.
In the infection and replication of virus, various viral components such as dsRNA can be recongnized by PRRs such as RIG-Ⅰ like receptors (RLRs). RLRs recognize the viral dsRNA, and then recruit a central adapter protein, designated virus-induced signaling adapter (VISA, also known as IPS-1, MAVS and CARDIF), which signals to different pathways. VISA associates with TRAF3, MITA and TBK1to activate IRF3by phosphorylation while VISA contemporarily interacts with TRAF2/TRAF6to activate IKK complex, leading to subsequent activation of another transcription factor, NF-κB. Activated IRF3and NF-κB translocate in nuclear and collaboratively trigger the expression of type ⅠIFN genes.
The regulation mechanism of host antiviral response is mediated by the modifications of cellular proteins, the major of which are ubiquitination and deubiquitination. To identify some new proteins which are involved in the regulation of cellular antiviral signaling through ubiquitination and deubiquitination, we chose pGL3-NF-κB as a reporter gene for screening a gene library. We found that transiently transfection of an E3ubiquitin ligase, TRIM4led to the significant activation of the NF-κB, ISRE, and IFNβ reporters, and increased the induction of type I interferons in SeV infection. Consistently, knockdown of endogenous TRIM4remarkably inhibited the production of SeV-induced type I interferons. Endogenous coimmunoprecipitation experiments also indicated that TRIM4associated with RIG-I, and the interaction of them was increased by the induction of viral infection. Further study showed that TRIM4collaboratively triggered the production of IFNs by the associating with RIG-Ⅰ and subsequently catalyzing the K63-linked ubiquitination of RIG-I. There are some new questions from our study, such as whether TRIM25, which was identified as an E3ubiquitin ligase which target RIG-Ⅰ for K63-linked ubiquitination of RIG-Ⅰ, could associate with TRIM4. Moreover, knockout mice of TRIM4should be generated to support our conclusion.
Another TRIM family member, TRIM21was identified playing a role as a regulator of IRF3signaling. However, two independent groups received the opposite conclusions. Yang et al demonstrated that TRIM21increases the stability of IRF3to enhance type I interferons induction by interaction with Pinl, a negative regulator of antiviral responses that mediates the ubiquitination and degradation of IRF3during virus infection. In contrast, Higgs et al found that TRIM21interacts with IRF3and promotes the ubiquitination and degradation of IRF3to limit IFNβ induction. Thus, to reveal the function of TRIM21in antiviral pathway, we generated TRIM21deficient mice. In our study, the embryonic fibroblast cells derived from TRIM21deficient mice showed increased production of IFNP and downstream gene RANTES in SeV infection. Our study confirmed that TRIM21in vivo inhibits in virus-induced production of type I IFNs, and the physiological molecular mechanism needs our further study. And comprehensive phenotype analysis of TRIM21deficient mice could furnish more information to us.
引文
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