MITA介导的细胞抗病毒反应信号转导及其调节机制
摘要
长期以来,病毒感染与宿主免疫的机制一直是生命科学领域的研究热点。病毒入侵宿主细胞后,首先被宿主模式识别受体(pattern-recognition receptors, PRRs)所识别,PRRs激活一系列的信号转导,诱导Ⅰ型干扰素和白细胞介素1β(interleukin 1-p, IL-1β)等细胞因子的表达。这些细胞因子分泌到细胞外,与细胞表面受体结合,激活相应的信号转导,诱导大量的抗病毒基因的表达,从而抑制病毒的复制,诱导被感染的细胞凋亡；同时,这些细胞因子诱导产生炎症反应,激活天然免疫细胞以及适应性免疫系统,从而杀灭病毒并清除病毒感染的细胞。因此,Ⅰ型干扰素等细胞因子的表达对宿主抵抗病毒入侵起着举足轻重的作用。
研究表明,病毒在感染与复制的过程中产生病原相关分子模式(pathogen-associated molecular patterns, PAMPs),如5’三磷酸具有锅柄状结构的RNA(5'ppp panhandle RNA)以及双链RNA (double-stranded RNA, dsRNA)。宿主细胞内的PRR如RIG-I(retinoic acid-inducible gene I)与MDA5(melanoma differentiation-associated gene 5)识别相应的PAMP后构象发生变化,招募定位于线粒体的接头蛋白VISA (virus-induced signaling adaptor)。VISA通过与TRAF6 (tumor necrosis factor receptor-associated factor 6)或TRAF2相互作用,激活IKK (inhibitor ofκB kinase)复合物,IKK复合物磷酸化IκB (inhibitor ofκB),使IKB经泛素-蛋白酶体途径降解,释放出转录因子NF-κB。同时VISA与TRAF3以及TBK1 (TRAF family member-associated NF-κB activator-binding kinase 1)相互作用,促进TBK1磷酸化激活IRF3 (interferon-regulatory factor 3)。激活的转录因子如IRF3与NF-κB进入细胞核结合至Ⅰ型干扰素等基因的启动子上,激活Ⅰ型干扰素的转录。
尽管最近十年的研究初步揭示了病毒感染诱导Ⅰ型干扰素产生的过程,但是仍然有很多未知的问题有待进一步研究。例如,VISA通过保守的TRAF相互作用位点与TRAF6和TRAF2相互作用激活NF-κB,而VISA如何与TBK1的相互作用并进一步激活IRF3则并不清楚。此外,DNA病毒的受体及其介导Ⅰ型干扰素的机制是什么,细胞中是否存在其它未知的激活Ⅰ型干扰素的蛋白等等。为了寻找参与激活Ⅰ型干扰素表达的蛋白,我们利用表达克隆的方法筛选了人脾脏cDNA表达文库,发现一个功能未知的蛋白能有效激活IRF3,我们将其命名为MITA (mediator of IRF3 activator)。研究表明,MITA能有效激活转录因子IRF3而不激活NF-κB。RNAi下调MITA的表达则抑制病毒诱导的IRF3和NF-κB的激活、IFN-β等抗病毒基因的表达以及细胞抗病毒反应。MITA的N端含有四个跨膜结构域,其中第三个跨膜结构域(aalll-150)对其线粒体定位、与VISA相互作用以及自身的多聚化非常重要,第二个跨膜结构与第三个跨膜结构之间的部分(aa81-110)对促进TBK1-IRF3相互作用是必须的。内源性免疫沉淀实验表明,MITA持续性地与VISA和IRF3相互作用,病毒感染后,MITA将TBK1招募至线粒体,介导VISA-TBK1-IRF3相互作用；同时,MITA通过自身多聚化形成VISA-MITA-TBK1-IRF3复合物。在这一复合物中,MITA第358位的丝氨酸被TBK1磷酸化,这一过程为IRF3的磷酸化激活所必需。
在研究MITA介导Ⅰ型干扰素表达机制的过程中,我们发现没有病毒感染的情况下MITA已经被磷酸化,但是哪(几)种蛋白介导静息状态下MITA磷酸化还不清楚；同时我们也观察到MITA能被泛素化,但是MITA泛素化的机制与意义也不清楚。为了回答上述问题,我们以MITA为“诱饵”蛋白进行了酵母双杂交实验,发现一个E3泛素连接酶RNF5能与MITA相互作用。RNF5的C端含有一个跨膜结构域,并通过其C端与MITA相互作用。RNF5在多种细胞中特异地抑制病毒感染引发的信号转导,包括293、HeLa以及原代巨噬细胞和树突状细胞(dendritic cells, DCs),并且其E3泛素连接酶活性对抑制信号转导过程是必需的。RNAi下调RNF5的表达则促进病毒感染引起的IRF3的激活以及IFN-P等抗病毒基因的表达。进一步的研究表明,病毒感染诱导RNF5在线粒体-内质网上动态分布,RNF5在线粒体上与MITA和VISA相互作用,并催化MITA第150位赖氨酸以及VISA第362和461位的赖氨酸残基发生泛素化,并使其通过蛋白酶体途径降解,从而负调节病毒感染早期的信号转导,以防止过度的免疫反应。
我们的研究发现了一个新的定位于线粒体并介导Ⅰ型干扰素表达的接头蛋白MITA,进一步阐述了病毒感染诱导Ⅰ型干扰素表达的机制；我们进一步的研究发现了定位于内质网和线粒体的E3泛素连接酶RNF5通过泛素化降解MITA和VISA,负调控病毒感染诱导的Ⅰ型干扰素的表达,防止免疫系统过度激活对宿主造成的伤害,也揭示亚细胞器线粒体-内质网之间的“交流”(interplay)在抵御病毒感染与防止过度免疫的平衡过程中扮演着非常重要的角色。
The mechanisms of viral infection and host immune response have long been recognized as a hot research field in life sciences. Pattern-recognition receptors (PRRs) encoded by the host genome recognize invading viruses, representing the first step for antiviral response. The PRRs initiates a series of signaling, which leads to production of a number of cytokines such as typeⅠinterferons (IFNs) and interleukin-1β(IL-1β). The secreted typeⅠIFNs bind to the receptors in autocrine or paracrine manner and initiate signaling that activates transcription of thousands of genes. The produced proteins collaborate to inhibit viral replication or induce apoptosis of infected cells. On the other hand, typeⅠIFNs activate innate immune cells to induce inflammatory response and/or adaptive immune system, resulting in clearance of invading virus and infected cells. Thus, typeⅠIFNs play a vital role in host antiviral response.
The mechanisms of virus-triggered induction of typeⅠIFNs have been extensively investigated during the past decade. Viral infection and replication generate pathogen associated molecular patterns (PAMPs) such as 5'triphosphate panhandle RNA and double-stranded RNA, which are recognized by the pattern-recognition receptors (PRRs). Among the PRRs, the cytoplasmic RIG-Ⅰ-like receptors (RLRs), RIG-I and MDA5, have been demonstrated to bind to viral RNAs. Upon detection of viral RNA, RIG-I or MDA5 is associated with the mitochondrial adaptor protein VISA. VISA is associated with several downstream proteins constitutively or in a viral infection dependent manner, including TRAF2, TRAF3 and TRAF6. On one hand, VISA interacts with TRAF2 and/or TRAF6 to activate IKK complex, which phosphorylates IκB. The phosphorylated IκB is ubiquitinated and degraded through proteasome, leading to the release and activation of NF-κB. On the other hand, VISA recruits TRAF3 and TBKl to phosphorylate and activate IRF3. The activated transcription factors IRF3 and NF-κB enter into the nucleus and collaboratively activate transcription of typeⅠIFN genes.
Although breakthrough advances on the virus-triggered typeⅠIFN signaling pathways have been made during the past decade, there are a lot of key questions remaining to be elucidated. For example, it has been suggested that VISA interacts with TRAF2/TRAF6 via its conserved TRAF-interacting motifs to activate NF-κB, whereas how VISA is associated with TBK1 to activate IRF3 is not known yet. Also, what are the unknown proteins involved in virus-triggered typeⅠIFN signaling is another research interest. To identify proteins involved in typeⅠIFNs production, we performed expression cloning experiments, leading to the identification and characterization of MITA (mediator of IRF3 activation). Overexpression of MITA activated IRF3, whereas knockdown of MITA inhibited virus-triggered activation of IRF3, expression of typeⅠIFNs, and cellular antiviral response. MITA contained four putative transmenbrane domains at its N-terminus and was found to localize to the outer membrane of mitochondria and the third transmembrane is critical for its mitochondrial localization, VISA-MITA association and MITA oligomerization. MITA was found to be associated with VISA and IRF3 constitutively and recruited the kinase TBK1 to the VISA-associated complex. The serine 358 of MITA was phosphorylated by TBK1, which is required for MITA-mediated activation of IRF3.
During the process to characterize MITA, we found that MITA was basally phosphorylated without viral infection. However, the kinase(s) remained to be identified. In addition, we also observed that MITA was ubiquitinated, whereas the mechanism of this process was unknown. To address these questions, we performed yeast two-hybrid assays with full-length MITA as bait, leading to the identification of an E3 ubiquitin ligase RNF5 as a MITA-interacting protein. RNF5 interacted with MITA through its C-terminus in a viral-infection-dependent manner. Overexpression of RNF5 inhibited virus-triggered IRF3 activation, IFN-βexpression and cellular antiviral response, whereas knockdown of RNF5 had opposite effects. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection. Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) and viral infection caused their redistribution to the ER and mitochondria, respectively. We further found that virus-induced ubiquitination and degradation of MITA by RNF5 occurred at the mitochondria. We also found that RNF5 targeted Lys 362 and Lys 461 of VISA for ubiquitination at the early phase of viral infection, thereby negatively regulating virus-induced type I IFN signaling and preventing excessive immune responses.
These studies further our understandings of the mechanisms and regulations of virus-induced type I IFN signaling and contribute to the elucidation of the complicated molecular mechanisms of cellular antiviral response. Our results also indicate that the interplay between mitochondria and ER plays a critical role in host defense against invading viruses as well as avoiding harmful excessive immune responses.
研究表明,病毒在感染与复制的过程中产生病原相关分子模式(pathogen-associated molecular patterns, PAMPs),如5’三磷酸具有锅柄状结构的RNA(5'ppp panhandle RNA)以及双链RNA (double-stranded RNA, dsRNA)。宿主细胞内的PRR如RIG-I(retinoic acid-inducible gene I)与MDA5(melanoma differentiation-associated gene 5)识别相应的PAMP后构象发生变化,招募定位于线粒体的接头蛋白VISA (virus-induced signaling adaptor)。VISA通过与TRAF6 (tumor necrosis factor receptor-associated factor 6)或TRAF2相互作用,激活IKK (inhibitor ofκB kinase)复合物,IKK复合物磷酸化IκB (inhibitor ofκB),使IKB经泛素-蛋白酶体途径降解,释放出转录因子NF-κB。同时VISA与TRAF3以及TBK1 (TRAF family member-associated NF-κB activator-binding kinase 1)相互作用,促进TBK1磷酸化激活IRF3 (interferon-regulatory factor 3)。激活的转录因子如IRF3与NF-κB进入细胞核结合至Ⅰ型干扰素等基因的启动子上,激活Ⅰ型干扰素的转录。
尽管最近十年的研究初步揭示了病毒感染诱导Ⅰ型干扰素产生的过程,但是仍然有很多未知的问题有待进一步研究。例如,VISA通过保守的TRAF相互作用位点与TRAF6和TRAF2相互作用激活NF-κB,而VISA如何与TBK1的相互作用并进一步激活IRF3则并不清楚。此外,DNA病毒的受体及其介导Ⅰ型干扰素的机制是什么,细胞中是否存在其它未知的激活Ⅰ型干扰素的蛋白等等。为了寻找参与激活Ⅰ型干扰素表达的蛋白,我们利用表达克隆的方法筛选了人脾脏cDNA表达文库,发现一个功能未知的蛋白能有效激活IRF3,我们将其命名为MITA (mediator of IRF3 activator)。研究表明,MITA能有效激活转录因子IRF3而不激活NF-κB。RNAi下调MITA的表达则抑制病毒诱导的IRF3和NF-κB的激活、IFN-β等抗病毒基因的表达以及细胞抗病毒反应。MITA的N端含有四个跨膜结构域,其中第三个跨膜结构域(aalll-150)对其线粒体定位、与VISA相互作用以及自身的多聚化非常重要,第二个跨膜结构与第三个跨膜结构之间的部分(aa81-110)对促进TBK1-IRF3相互作用是必须的。内源性免疫沉淀实验表明,MITA持续性地与VISA和IRF3相互作用,病毒感染后,MITA将TBK1招募至线粒体,介导VISA-TBK1-IRF3相互作用；同时,MITA通过自身多聚化形成VISA-MITA-TBK1-IRF3复合物。在这一复合物中,MITA第358位的丝氨酸被TBK1磷酸化,这一过程为IRF3的磷酸化激活所必需。
在研究MITA介导Ⅰ型干扰素表达机制的过程中,我们发现没有病毒感染的情况下MITA已经被磷酸化,但是哪(几)种蛋白介导静息状态下MITA磷酸化还不清楚；同时我们也观察到MITA能被泛素化,但是MITA泛素化的机制与意义也不清楚。为了回答上述问题,我们以MITA为“诱饵”蛋白进行了酵母双杂交实验,发现一个E3泛素连接酶RNF5能与MITA相互作用。RNF5的C端含有一个跨膜结构域,并通过其C端与MITA相互作用。RNF5在多种细胞中特异地抑制病毒感染引发的信号转导,包括293、HeLa以及原代巨噬细胞和树突状细胞(dendritic cells, DCs),并且其E3泛素连接酶活性对抑制信号转导过程是必需的。RNAi下调RNF5的表达则促进病毒感染引起的IRF3的激活以及IFN-P等抗病毒基因的表达。进一步的研究表明,病毒感染诱导RNF5在线粒体-内质网上动态分布,RNF5在线粒体上与MITA和VISA相互作用,并催化MITA第150位赖氨酸以及VISA第362和461位的赖氨酸残基发生泛素化,并使其通过蛋白酶体途径降解,从而负调节病毒感染早期的信号转导,以防止过度的免疫反应。
我们的研究发现了一个新的定位于线粒体并介导Ⅰ型干扰素表达的接头蛋白MITA,进一步阐述了病毒感染诱导Ⅰ型干扰素表达的机制；我们进一步的研究发现了定位于内质网和线粒体的E3泛素连接酶RNF5通过泛素化降解MITA和VISA,负调控病毒感染诱导的Ⅰ型干扰素的表达,防止免疫系统过度激活对宿主造成的伤害,也揭示亚细胞器线粒体-内质网之间的“交流”(interplay)在抵御病毒感染与防止过度免疫的平衡过程中扮演着非常重要的角色。
The mechanisms of viral infection and host immune response have long been recognized as a hot research field in life sciences. Pattern-recognition receptors (PRRs) encoded by the host genome recognize invading viruses, representing the first step for antiviral response. The PRRs initiates a series of signaling, which leads to production of a number of cytokines such as typeⅠinterferons (IFNs) and interleukin-1β(IL-1β). The secreted typeⅠIFNs bind to the receptors in autocrine or paracrine manner and initiate signaling that activates transcription of thousands of genes. The produced proteins collaborate to inhibit viral replication or induce apoptosis of infected cells. On the other hand, typeⅠIFNs activate innate immune cells to induce inflammatory response and/or adaptive immune system, resulting in clearance of invading virus and infected cells. Thus, typeⅠIFNs play a vital role in host antiviral response.
The mechanisms of virus-triggered induction of typeⅠIFNs have been extensively investigated during the past decade. Viral infection and replication generate pathogen associated molecular patterns (PAMPs) such as 5'triphosphate panhandle RNA and double-stranded RNA, which are recognized by the pattern-recognition receptors (PRRs). Among the PRRs, the cytoplasmic RIG-Ⅰ-like receptors (RLRs), RIG-I and MDA5, have been demonstrated to bind to viral RNAs. Upon detection of viral RNA, RIG-I or MDA5 is associated with the mitochondrial adaptor protein VISA. VISA is associated with several downstream proteins constitutively or in a viral infection dependent manner, including TRAF2, TRAF3 and TRAF6. On one hand, VISA interacts with TRAF2 and/or TRAF6 to activate IKK complex, which phosphorylates IκB. The phosphorylated IκB is ubiquitinated and degraded through proteasome, leading to the release and activation of NF-κB. On the other hand, VISA recruits TRAF3 and TBKl to phosphorylate and activate IRF3. The activated transcription factors IRF3 and NF-κB enter into the nucleus and collaboratively activate transcription of typeⅠIFN genes.
Although breakthrough advances on the virus-triggered typeⅠIFN signaling pathways have been made during the past decade, there are a lot of key questions remaining to be elucidated. For example, it has been suggested that VISA interacts with TRAF2/TRAF6 via its conserved TRAF-interacting motifs to activate NF-κB, whereas how VISA is associated with TBK1 to activate IRF3 is not known yet. Also, what are the unknown proteins involved in virus-triggered typeⅠIFN signaling is another research interest. To identify proteins involved in typeⅠIFNs production, we performed expression cloning experiments, leading to the identification and characterization of MITA (mediator of IRF3 activation). Overexpression of MITA activated IRF3, whereas knockdown of MITA inhibited virus-triggered activation of IRF3, expression of typeⅠIFNs, and cellular antiviral response. MITA contained four putative transmenbrane domains at its N-terminus and was found to localize to the outer membrane of mitochondria and the third transmembrane is critical for its mitochondrial localization, VISA-MITA association and MITA oligomerization. MITA was found to be associated with VISA and IRF3 constitutively and recruited the kinase TBK1 to the VISA-associated complex. The serine 358 of MITA was phosphorylated by TBK1, which is required for MITA-mediated activation of IRF3.
During the process to characterize MITA, we found that MITA was basally phosphorylated without viral infection. However, the kinase(s) remained to be identified. In addition, we also observed that MITA was ubiquitinated, whereas the mechanism of this process was unknown. To address these questions, we performed yeast two-hybrid assays with full-length MITA as bait, leading to the identification of an E3 ubiquitin ligase RNF5 as a MITA-interacting protein. RNF5 interacted with MITA through its C-terminus in a viral-infection-dependent manner. Overexpression of RNF5 inhibited virus-triggered IRF3 activation, IFN-βexpression and cellular antiviral response, whereas knockdown of RNF5 had opposite effects. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection. Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) and viral infection caused their redistribution to the ER and mitochondria, respectively. We further found that virus-induced ubiquitination and degradation of MITA by RNF5 occurred at the mitochondria. We also found that RNF5 targeted Lys 362 and Lys 461 of VISA for ubiquitination at the early phase of viral infection, thereby negatively regulating virus-induced type I IFN signaling and preventing excessive immune responses.
These studies further our understandings of the mechanisms and regulations of virus-induced type I IFN signaling and contribute to the elucidation of the complicated molecular mechanisms of cellular antiviral response. Our results also indicate that the interplay between mitochondria and ER plays a critical role in host defense against invading viruses as well as avoiding harmful excessive immune responses.
引文
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