UBIQUITINATION-MEDIATED REGULATION OF RLR-TRIGGERED ANTIVIRAL SIGNALING IN FISH AND MAMMALS
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摘要: RLR[retinoic acid-inducible gene Ⅰ(RIG-Ⅰ)-like Receptors]是一类表达在胞浆中的模式识别受体, 在识别细胞质中经病毒复制产生的病毒RNA后, 启动一系列信号级联反应, 以诱导机体Ⅰ型干扰素及干扰素诱导的抗病毒基因的表达, 最后达到清除机体病毒感染的目的。由于在病毒感染时机体干扰素反应必须迅速启动, 当病毒清除后干扰素反应又需要立即恢复到正常本底水平, 因此RLR激活的信号转导途径受到了严格的调控, 其中就包括由E3泛素连接酶参与的泛素化修饰调控和由去泛素化酶参与的去泛素化修饰调控。自2003年成功鉴定出鱼类干扰素基因以来, 鱼类也被发现具有保守的RLR信号转导途径诱导干扰素抗病毒免疫反应, 该信号途径同样受到泛素化修饰的调控。文章总结了近年来泛素化修饰在哺乳类和鱼类RLR介导的抗病毒免疫应答通路中的调节机制。Abstract: In mammals, type I interferon (IFN) response is the first line of defense against viral invasion. In the case of viral infection, host cells recognize the corresponding pathogen-associated molecular pattern (PAMPs) by pathogen recognition receptor (PRRs) and recruit different downstream linker molecules to initiate the corresponding signal transduction pathway, eventually resulting in the expression of IFN, which in turn activates the transcription of numerous downstream IFN-stimulated gene (ISG) expression for establishment of host antiviral immune state. RLR [retinoic acid-inducible gene I (RIG-I)-like Receptors] represents a family of cytosolic pattern recognition receptors, composed of RIG-I, MDA5 (Melanoma differentiation-associated gene 5) and LGP2 (Laboratory of genetics and physiology 2). RLR receptors are structurally highly conserved and contain a DEX (D/H)-box RNA helicase domain and a C-terminal RNA binding domain and regulatory domain. Compared to RIG-I and MDA5, LGP2 shares the helicase domain and RD but lacks the two N-terminal CARDs that are required for RLR-triggered IFN signaling. Extensive studies have suggested a canonical paradigm of RIG-I and MDA5 signaling. Upon binding to 5’ppp- or 5’pp-dsRNA through RD and helicase domain, RIG-I undergoes a conformational change, thus releasing N-terminal CARDs from an auto-inhibitory state in an ATP-dependent manner and initiating downstream signaling cascade after interaction with adaptor mitochondrial antiviral signaling protein (MAVS). MDA5 preferentially binds to long dsRNAs to form protein-coated filaments, therefore leading to tandem CARDs oligomerization to activate MAVS. The resultant MAVS activation finally facilitates protein kinases TANK-binding kinase 1 (TBK1) to phosphorylate and activate IFN regulatory factors 3/7 (IRF3/7). The phosphorylated IRF3/7 translocate from cytoplasm to nucleus, bind to the promoters of IFN genes, and turn on their expression. The secreted IFNs combine to the cognate receptors in an autocrine or a paracrine manner, to activate the JAK-STAT pathway inducing the expression of ISGs. Upon some RNA virus infection, mediator of IRF3 activation (MITA) also functions as a scaffold protein to link TBK1 and IRF3 to MAVS complex for the expression of IFN and ISGs, although it is well-known that MITA primarily participates in virus DNA-directed IFN signaling. As the third member of RLR family, LGP2 is initially considered to be dysfunctional. Recent studies have shown that LGP2 is a key factor for regulation of a switch between positive and negative roles in RLR signal transduction: at lower levels, LGP2 synergies with MDA5 but not RIG-I to augment IFN signaling; at higher levels, LGP2 instead acts as an inhibitor of RIG-I and MDA5 signaling. Many ISGs encode antiviral effector proteins that are essential for eradication of virus invasion. Which beneficial for host cells to rapidly turn on the expression of IFN and ISGs upon viral infection, overproduction of IFNs leads to the development of immunopathological conditions partially due to continuous expression of those IFN-induced antiviral proteins. Therefore, it is important for host cells to immediately terminate the IFN-mediated antiviral response after virus has been cleared. That is, RLR-triggered IFN antiviral response should be fine tune controlled at an appropriate extent as relative to that of viral infection in given cells. Consistently, host cells develop multiple mechanisms to precisely modulate IFN signaling for appropriate production of IFNs. Actually, some factors display abilities to appropriately regulate RLR-triggered IFN signaling. They include E3-ubiquintin ligases and deubiquitinases (DUBs), which mediate ubiquitination or deubiquitination of targeted signaling components of RLR pathway to cooperatively regulate their biological activity. A best example is the family of tripartite motif (TRIM) proteins, which play pivotal roles in the innate antiviral response. Generally, TRIMs function as a major class of E3 ubiquitin ligase enzymes, and work together with ubiquitin-activating enzymes (E1s) and ubiquitin-conjugating enzymes (E2s) to participate in an ubiquitination cascade process. Such process results in diverse ubiquitination modifications of RLR signaling factors, to activate them from an inactive state, or target them to degrade by proteasome or lysosomal pathways, thus regulating RLR-triggered IFN antiviral response. Notably, ubiquitination modification process is inducible and also is reversible. In the case, many deubiquitinases, including ubiquitin-specific proteases (USP) and ovarian tumor protein (OUT), are capable to remove the related ubiquitination-mediated modification from the targeted proteins, finally convert the E3 ligase-mediated ubiquitination to shape IFN antiviral response at a given infection time. Since the first fish IFN gene was identified in zebrafish in 2003, accumulating evidence has shown that fish exist the conserved RLR-mediated IFN signaling pathway. Although fish IFNs are not classified into IFNα/β but instead group I and group II IFNs based on cysteine numbers, fish RIG-I and MDA-5 direct IFN expression through a conserved RIG-I/MDA5-MAVS/MITA-TBK1-IRF3/7 signaling pathway. In addition, fish LGP2 confers protection on fish cells against SVCV infection through a similar signaling pathway and at limited expression levels, LGP2 exerts more significant protection than either RIG-I or MDA5. Importantly, RLR-triggered fish IFN antiviral response is also regulated appropriately by similar mechanisms, in which ubiquitination- and deubiquitination-mediated regulation is involved. In this review, we summarize the recent progress on ubiquitination-mediated regulation of RLR-triggered IFN antiviral response in mammals and fish.
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Keywords:
- RLR /
- E3-ubiquitin ligase /
- Deubiquitinase /
- Ubiquitination /
- Deubiquitination
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近20多年来, 识别病毒感染信号的细胞受体的发现, 加深了我们在分子水平上对干扰素(Interferon, IFN)抗病毒免疫反应机制的理解。病毒在细胞中复制产生的病毒核酸, 称为病原相关分子模式(Pathogen-associated molecular patterns, PAMPs), 能快速被宿主细胞表达的受体分子, 称为模式识别受体(Pattern recognition receptors, PRRs)所识别, 然后激活一连串的信号级联反应, 最后诱导机体细胞IFN、促炎因子和其他下游效应蛋白的表达, 清除病毒在细胞中的感染[1]。机体IFN介导的抗病毒免疫反应需要适度启动和激发, 因此在应对病毒感染时, 在不同的细胞类型、不同的感染时间都受到不同机制参与的精确调控。
1. RLR介导的IFN抗病毒免疫通路
哺乳类细胞主要表达两类模式识别受体, 用于感知病毒RNA诱导IFN抗病毒免疫反应: 表达于内吞体(Endosome)膜上的TLR3/7/8/9(Toll-like receptor 3, 7, 8, 9)和表达于胞浆中的RLR受体。前者识别细胞内吞病毒后产生的病毒RNA, 后者识别病毒复制时在细胞质中产生的RNA。RLR受体家族有三个成员: RIG-Ⅰ (Retinoic acid-inducible gene Ⅰ)、MDA5 (Melanoma differentiation-associated protein 5)和LGP2(Laboratory of genetics and physiology 2)。TLR受体一般在免疫细胞中表达, 而RIG-Ⅰ和MDA5在大多数细胞类型中都表达, 只是在没有病毒入侵时表达量很低, 但在病毒感染后被大量诱导表达[1]。因此, 在IFN抗病毒免疫反应中RLR信号受到更多的关注和研究。RIG-Ⅰ和MDA5蛋白包含两个N端半胱天冬酶激活和募集结构域(Caspase activation and recruitment domain, CARD), 主要负责将受体感知信号传导到下游分子; 此外, 还有一个中央DExD/H-box解旋酶结构域和一个C末端结构域(C-terminal domain, CTD), 在识别和结合病毒RNA中发挥重要作用[2]。与RIG-Ⅰ和MDA5相比, LGP2缺乏N端的CARD结构域, 通常被认为在RLR信号传导中起调节作用[3]。
自2003年在斑马鱼中首次鉴定出第一个鱼类ifn基因后, 鱼类干扰素介导的抗病毒免疫反应研究获得了重要进展[4－6]。鱼类同样存在RLR介导的抗病毒免疫反应途径[7－9]。尽管还缺乏很多直接的实验证据, 但是目前的研究表明, 鱼类RIG-Ⅰ和MDA5一旦结合了病毒RNA之后, 就会与定位于线粒体上的关键接头蛋白MAVS (Mitochondrial antiviral-signaling, 也被称为VISA, CARDIF和IPS-1)结合。MAVS作为一个信号平台, 继续招募并激活蛋白激酶TBK1(TANK binding kinase 1), 激活后的TBK1随即磷酸化激活转录因子IRF3(IFN regulatory factor 3)和IRF7, 并促使IRF3/7从细胞质进入到细胞核与ifn基因启动子结合, 从而启动ifn基因的转录表达。表达的IFN蛋白分泌到细胞外, 然后通过自分泌和旁分泌途径, 与感染病毒的细胞和未感染细胞的细胞膜上的IFN受体结合, 激活下游的JAK-STAT(Janus kinase-Signal Transducer and Activator of Transcription)信号通路, 最终诱导下游干扰素刺激基因(IFN-stimulated genes, ISGs)的表达。有些ISG编码抗病毒蛋白, 如Mx、PKR和ISG15等, 直接发挥抗病毒作用[10－13]; 而有些ISG编码蛋白依据其被病毒诱导表达的时空规律, 在不同细胞中和不同感染阶段, 对RLR介导的IFN抗病毒反应发挥调控作用[14, 15], 适时协调机体触发的IFN反应水平与病毒感染程度达到最佳平衡状态。一方面避免因IFN反应不足导致病毒不易消除干净, 另一方面也避免因过度反应导致机体产生自身免疫性疾病的情况发生。因此, RLR介导的IFN信号途径受到多方面的严格调控, 其中就包括由泛素化和去泛素化介导的翻译后修饰调控。
2. 泛素化与去泛素化修饰
泛素(Ubiquitin, Ub)是20世纪60年代发现的一个在信号转导中发挥调控作用的小蛋白分子。泛素分子可以通过E1-泛素活化酶(Ubiquitin-activating enzyme, E1)、E2-泛素结合酶(Ubiquitin-conjugating enzyme, E2)、E3-泛素蛋白连接酶(Ubiquitin-ligation enzyme, E2) 等三种酶参与的级联反应对底物蛋白进行泛素化修饰、以及在去泛素化酶(deubiquitinases, DUBs)的参与下发生底物蛋白的去泛素化。这种以可逆、可诱导的方式对底物蛋白进行的泛素化和去泛素化修饰几乎能调节细胞内所有重要的生命活动[16, 17]。泛素可以单分子或以多分子形成聚合物链的形式附着于底物蛋白的赖氨酸残基上, 称为泛素化修饰。在聚合物链中, 连续的泛素分子通过特定的肽键连接。多聚泛素链的形成依赖于泛素蛋白的赖氨酸残基。泛素蛋白由76个氨基酸组成, 其N端第一个氨基酸蛋氨酸(M1)和所有7个赖氨酸(K6、K11、K27、K29、K33、K48和K63)都可以作为受体位点, 在E1-泛素活化酶和E2-泛素结合酶的作用下聚合成不同类型的泛素链。E3-泛素蛋白连接酶则决定泛素链与特异性底物的结合, 从而改变底物蛋白的细胞定位以及蛋白活性[16, 17]。
在哺乳动物细胞中, 目前已发现2个E1(Uba1, 又称Ube1和Uba6), 40多个E2以及600多个E3。E3泛素连接酶按照结构特点主要有四类: RING(Really interesting new gene)结构域家族、HECT结构域家族(Homologous to E6-associated protein C-terminus)、RBR蛋白家族(RING-in-between RING)和RING拓扑结构类似的U-box蛋白家族(UFD2 homology)。RING E3泛素连接酶可以细分为单分子RING E3和多亚基E3复合物, 如SCF、APC/C、Cullin 2/Elongin B/C/VHL等均属于多亚基E3复合物。目前研究得比较清楚的是, K63位聚合泛素链(K63-linked polyubiquitination)修饰底物通常活化底物, 而K48位泛素化修饰则导致底物降解。因为泛素基团可以通过泛素分子中的八个残基位点进行连接, 因此为多聚泛素链种类的多样性提供了无限可能[16], 导致底物蛋白产生各种不同的泛素化修饰, 从而对IFN抗病毒免疫反应进行实时精确调控。
人类去泛素化酶基因有近100种, 可分为以下六种类型: 泛素特异型加工蛋白酶家族(Ubiquitin-specific processing enzymes, UBPs或Ubiquitin-specific proteases, USPs, 共54个家族成员), 泛素羧基末端水解酶家族(Ubiquitin C-terminal hydrolases, UCHs, 4个成员), Josephin结构域蛋白酶家族(4个成员), 卵巢肿瘤相关蛋白酶家族(Ovarian tumor protein, OUT, 16个成员), MINDY家族(the motif interacting with ubiquitin (MIU)-containing novel DUB family, 4个成员), 以及JAMM金属蛋白酶家族(Zn-dependent JAB1/MPN/MOV34 metalloprotease, 也称为MPN+, 16个成员)。去泛素化酶通过水解泛素羧基末端的酯键、肽键或异肽键, 将泛素分子特异性地从链接有泛素的蛋白质或者前体蛋白水解下来, 也就是对底物蛋白的泛素化进行反向调节, 最终影响蛋白功能。
3. RLR通路中的泛素化修饰调控
3.1 RIG-Ⅰ
哺乳类RIG-Ⅰ的泛素化修饰调控 2004年, RIG-Ⅰ被鉴定是一个重要的识别胞浆病毒核酸的模式识别受体[18]。RIG-Ⅰ的磷酸化和泛素化之间存在着串扰互作, 直接调节RIG-Ⅰ介导的下游信号转导。在正常细胞中, RIG-Ⅰ的CARD和CTD结构域受到强烈磷酸化, RIG-Ⅰ处于“自身抑制”的无活性状态, 此时RIG-Ⅰ的泛素化修饰程度也最低。在病毒感染的细胞中, RIG-Ⅰ的DExD/H-box和CTD结构域与病毒RNA结合, 很快发生去磷酸化, 随及触发RIG-Ⅰ的K63位泛素化修饰, 导致RIG-Ⅰ被激活, 从而将病毒感染信号通过MAVS向下游途径传递, 最终诱导IFN及ISG的表达。Oshiumi等[19]认为两个E3泛素连接酶 TRIM25(Tripartite motif 25)和Riplet(又称为RNF135, ring finger protein 135, 或REUL, RIG-Ⅰ E3 ubiquitin ligase)参与了RIG-Ⅰ的泛素化激活(图 1)。TRIM25的功能在2007年由Gack等[20]首次发现。鉴于RIG-Ⅰ在无病毒感染时N端的2个CARD结构被C端结构域所掩藏, RIG-Ⅰ处于一种“自身抑制”的无活性状态, Gack等[20]用GST-RIG-Ⅰ(2CARD)(即只有N端的2个CARD结构域)来代替全长的RIG-Ⅰ开展实验。他们由此发现TRIM25介导RIG-Ⅰ蛋白的第二个CARD结构域中的K172氨基酸发生K63泛素化, 且发现RIG-Ⅰ(2CARD)必须先产生泛素化修饰后才能被激活, 然后启动信号转导[21]。随后Zeng等[22]通过体外的生化重构实验证实了TRIM25能泛素化激活RIG-Ⅰ( 2CARD)信号转导的事实。
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图 1 鱼类和哺乳类RLR介导的抗病毒免疫反应的泛素化修饰调控蓝色和红色箭头分别代表对RLR关键分子的正、负调控作用。深色椭圆及文字标明了泛素化和去泛素化的类型, 其中“+”和“−”分别表示对不同类型的泛素链的泛素化和去泛素化作用。根据所查阅的文献, 图中只列出了在相关调控方面研究较为清楚的RLR成员以及介导的(去)泛素化的调控机制Figure 1. (De) ubiquitination-mediated regulation of antiviral immune RLR-signaling pathway in mammal and fishThe blue and red arrows in the figure represent the positive and negative regulatory effects on the key molecules of RLR signaling, respectively. Dark ellipses with text indicate the types of ubiquitin chains that are added to or removed from the targeted proteins (“+”: ubiquitination; “−”: deubiquitination). According to the literature consulted, only the RLR members with detailed regulatory mechanisms are listed需要指出的是, 由于转染RIG-Ⅰ的N端CARD结构域就能成功模拟RIG-Ⅰ介导IFN反应的信号转导过程, 因此, 泛素化修饰的研究最初使用的是截短的N端CARDs, 而不是野生型的全长RIG-Ⅰ[19－22]。然而, 这种研究方式的缺陷逐渐显露出来。后续的比较研究发现, 过量表达TRIM25能激活全长RIG-Ⅰ蛋白介导的IFN信号, 但是激活的信号强度远小于激活RIG-Ⅰ( 2CARD)介导的信号, 而且发现另外一种E3泛素连接酶Riplet/RNF135在TRIM25激活全长RIG-Ⅰ的信号通路中发挥作用[19]。与TRIM25结合并泛素化RIG-Ⅰ的CARD不同, Riplet/RNF135直接结合并泛素化RIG-Ⅰ蛋白的C端RD结构域(735—925 aa), 从而释放RIG-Ⅰ蛋白 RD(Repression domain)对CARDs的自我抑制[19]。Riplet能促进TRIM25与全长RIG-Ⅰ蛋白之间的互作, 因为RIG-Ⅰ蛋白K788R位点的突变不仅削弱Riplet介导的RIG-Ⅰ泛素化, 而且严重影响TRIM25与全长RIG-Ⅰ蛋白之间的互作。因此, Oshiumi等[19]认为, Riplet介导的RIG-Ⅰ蛋白C端RD的聚泛素化修饰是TRIM25激活RIG-Ⅰ的先决条件。然而, 在2019年的一项研究中, Cadena等[23]发现野生型全长RIG-Ⅰ蛋白的泛素化修饰激活绝对依赖于Riplet而不是TRIM25。基因敲除实验发现, TRIM25有无对于全长RIG-Ⅰ信号传导没有影响, 仅对GST-2CARD的信号传导有中等刺激作用。鉴于Riplet基因缺失不影响GST-2CARD介导的信号传导, 因此, GST-2CARD介导的信号传导机制完全不同于全长RIG-Ⅰ蛋白介导的信号转导[23]。
质谱分析表明, RIG-Ⅰ蛋白CRAD的结构域中K99、K169、K172、K181、K190和K193位点都存在K63泛素化修饰[20]。除TRIM25外, TRIM4[24]和MEX3C[25]也通过K63泛素化修饰CARD结构域活化RIG-Ⅰ。此外, RIG-Ⅰ还受到其他泛素连接酶的修饰调控。如RNF125介导RIG-Ⅰ的K48泛素化, 导致RIG-Ⅰ通过蛋白酶体途径降解, 以免宿主产生过度IFN反应引起自身免疫性疾病[26]。RNF122对K115和K146氨基酸位点的K48泛素化修饰最终驱动RIG-Ⅰ蛋白的降解[27]。TRIM40与RIG-Ⅰ和MDA5蛋白靶向结合, 通过E3连接酶活性促进K27和K48连接的多聚泛素化, 导致靶定蛋白通过蛋白酶体途径降解。因此, TRIM40缺失则增强宿主的抗病毒免疫反应[28]。有报道E3连接酶CHIP[29]、STUB-1[30]和c-Cbl[31]也通过K48泛素化修饰底物RIG-Ⅰ蛋白、促进后者降解。
RIG-Ⅰ也受到了由去泛素化酶介导的去泛素化修饰的调节作用。CYLD(Cylindromatosis, 头帕肿瘤综合征蛋白)[32]和USP14[33]是一种去泛素化酶, 能特异性去除RIG-Ⅰ蛋白的K63位泛素化链, 因此是一种调控RIG-Ⅰ信号的负调节因子。在poly(I:C)处理和VSV感染的细胞中, USP3被招募与RIG-Ⅰ结合, 特异性消除RIG-Ⅰ的K63位泛素化链[34]。在没有病毒感染时, USP21能结合RIG-Ⅰ并消除蛋白中已发生的K63位泛素修饰[35]。此外, USP4则靶向RIG-Ⅰ发生K48泛素化介导的蛋白降解作用, 通过消除K48泛素化、稳定细胞RIG-Ⅰ的表达[36]。
鱼类RIG-Ⅰ的泛素化修饰调控 鱼类RIG-Ⅰ同样受到E3泛素连接酶的修饰调控。最近的一份研究认为斑马鱼中也存在一个Riplet/RNF135同源基因, 在斑马鱼的不同组织中广泛表达, poly(I:C)模拟病毒感染能诱导斑马鱼该基因的表达上调。免疫共沉淀实验证实该斑马鱼基因编码蛋白能与RIG-Ⅰ结合。在体外培养细胞中, 过量表达该基因导致斑马鱼RIG-Ⅰ的K63连锁泛素化, 同时也促进斑马鱼RIG-Ⅰ介导的IFN启动子的激活。这些研究结果表明, 斑马鱼RNF135同源基因具有保守的功能, 通过调节斑马鱼RIG-Ⅰ信号通路参与了先天免疫应答[37]。我们分析目前版本的斑马鱼基因组后, 发现斑马鱼Riplet/RNF135基因的编码蛋白与人Riplet/RNF135基因的一个缺少RING结构域的转录剪切体相似。斑马鱼Riplet/RNF135基因只编码一个由262氨基酸组成的蛋白, 与人和小鼠Riplet/RNF135编码蛋白长度为433个和417个氨基酸相比, 斑马鱼Riplet/RNF135蛋白缺少N端的RING结构域(该结构域通常赋予蛋白的E3泛素连接酶活性), 而人Riplet/RNF135蛋白如果缺失RING结构域, 不能泛素化修饰全长RIG-Ⅰ蛋白, 但依然能中等激活RIG-Ⅰ介导的IFN信号[23]。斑马鱼TRIM25有与哺乳类TRIM25相似的功能。在哺乳类中，TRIM25泛素化修饰RIG-Ⅰ蛋白的CARD结构域[21], 而在斑马鱼中体外实验表明, TRIM25通过K63泛素化修饰RIG-Ⅰ蛋白的CARD和RD结构域, 上调干扰素介导抗病毒免疫信号[38]。考虑到Riplet和TRIM25对哺乳类RIG-Ⅰ蛋白泛素化活化存在矛盾认识, 进一步开展鱼类RIG-Ⅰ的泛素化研究非常有必要。
3.2 MDA5
哺乳类MDA5的泛素化修饰调控 作用于RIG-Ⅰ的E3泛素连接酶TRIM40, 同样也结合MDA5, 并发生K27和K48连接的多聚泛素化修饰、促进MDA5通过蛋白酶体降解。RNF125也能诱导MDA5的K48连接的泛素化并使其降解, 因此负调控RLR介导的信号转导[26]。TRIM65与MDA5结合, 并在MDA5蛋白的K743位点上发生K63泛素化修饰。这种修饰仅对RLR受体中的MDA5的寡聚化和激活至关重要, 因为缺失TRIM65消除了脑心肌炎病毒(EMCV)诱导的IRF3激活和IFN的产生, 但对RIG-Ⅰ和TLR3介导的信号没有影响[39]。作为一种E3泛素连接酶, TRIM13抑制MDA5介导的IFN产生。基因敲除实验表明, EMCV感染的TRIM13−/−小鼠分泌更多的Ⅰ型IFN, 具有更强的病毒抵抗力, 因此获得更高的存活率[40]。TRIM25除介导RIG-Ⅰ蛋白N端CARD的外, 也K63泛素化修饰MDA5蛋白的CARD结构域[41]。
MDA5的去泛素化调控研究表明, USP13能消除RIG-Ⅰ和MDA5的K63位泛素化链修饰, 从而负调控RLR介导的抗病毒免疫反应[34]。体外实验表明USP17是一种去泛素化酶, 能抑制RIG-Ⅰ、MDA5、MITA、MAVS、IKKε和TRAF3等RLR信号分子的泛素化水平, 促进仙台病毒Sev激活的干扰素反应[42]。但机制是否因抑制K48泛素化修饰驱动RIG-Ⅰ和MDA5蛋白的降解还有待研究。
鱼类MDA5的泛素化修饰调控 石斑鱼(Epinephelus coioides)的几个TRIM家族基因已被成功鉴定, 如TRIM13和TRIM62基因的同源物[43, 44]。过量表达TRIM13或TRIM62能抑制MDA5介导的IFN信号, 也能促进石斑鱼神经坏死病毒(RGNNV)在培养细胞中的复制。由于TRIM家族蛋白的N端具有RING(Really interesting new gene)结构域, 该结构域一般赋予TRIM蛋白有E3泛素连接酶活性, 因此推测TRIM13和TRIM62的负调控作用可能与其E3泛素连接酶活性有关。事实上, RING结构域的缺失导致TRIM13负调控作用的丧失[43]。但是否因TRIM13和TRIM62的E3泛素连接酶活性直接导致鱼类MDA5的泛素化修饰还没有实验证据。
3.3 MAVS
哺乳类MAVS的泛素化修饰调控 2005年, 四个实验室同时鉴定MAVS基因为RLR受体转导信号的重要接头蛋白, 因此该基因有4个不同名称, MAVS、Cardif、IPS-1和VISA[1]。MAVS是一个由 540个氨基酸组成的蛋白, 包含N端的CARD结构域, 中间的脯氨酸富集结构域(Proline-rich domain)和C端的跨膜结构域(Transmembrane domain)。跨膜结构域将MAVS蛋白锚定于线粒体外膜, CARD结构域与RIG-Ⅰ和MDA-5分子的CARD互作使它们被结合在一起, 随后MAVS继续招募TRAF(TNF receptor associated factor)和TBK1等下游信号蛋白, 活化转录因子IRF3和NF-κB, 进而诱导下游抗病毒基因的表达[45]。
与研究RIG-Ⅰ泛素化修饰调控的结果一致, MAVS被激活首先需要形成蛋白聚集体[45]。RIG-Ⅰ蛋白在N端CARD结构域经K63位泛素化链修饰后, 聚集形成带有四个串联CARDs的RIG-Ⅰ四聚体, 该四聚体进而做为平台起始MAVS聚集体的成核化[46]。多种泛素连接酶参与MAVS的泛素化修饰调控。如TRIM31催化MAVS蛋白K63连接的泛素化、促进MAVS寡聚化激活以及下游蛋白激酶TBK1的招募[47]。 HECT(Homologous to the E6AP carboxyl terminus)E3泛素连接酶家族的AIP4(ADP-ribosylation factor-like 6 interacting protein 4, 也称为ITCH, itchy E3 ubiquitin protein ligase)则催化MAVS的K48泛素化修饰, 导致MAVS通过蛋白酶体途径降解[48]。同属于HECT家族成员的Smurf1[49](SMAD specific E3 ubiquitin protein ligase 1, Nedd4家族四成员之一)和Smurf2[50]、以及MARCH5 [membrane-associated ring finger (C3HC4) 5] [51]也能介导MAVS的K48位泛素化链修饰影响MAVS蛋白的稳定性。Sev病毒感染促进RNF5(Ring finger protein 5)介导MAVS在K362和K461位点发生K48连接的泛素化修饰, 因此敲降RNF5基因能在早期逆转Sev引起的MAVS蛋白水平下调[52]。此外, 抗病毒蛋白Tetherin [又称BST2(Bone marrow stromal cell antigen 2)/CD317]通过募集E3泛素连接酶MARCH8, 介导MAVS的K27泛素化链修饰, 引导MAVS自噬降解, 从而抑制宿主过度的IFN反应[53]。TRIM21介导MAVS的K27位泛素化和活化[54], TRIM29介导MAVS的K11位泛素化修饰和降解[55]。
有意思的是, TRIM25既通过K63泛素化修饰活化RIG-Ⅰ[22], 又诱导MAVS的K48位泛素化修饰和降解[56]。后续对宿主蛋白Cyclophilin A(CypA, 亲环素A, 一种肽基脯氨酰顺反异构酶)的研究似乎可以解释TRIM25对RIG-Ⅰ和MAVS作用机理的不同。在Sev感染的细胞中, CypA与RIG-Ⅰ互作, 增强RIG-Ⅰ与TRIM25之间的结合、促进TRIM25介导的RIG-Ⅰ的K63泛素化、招募更多的RIG-Ⅰ与线粒体上的MAVS结合, 同时通过与TRIM25竞争性地与MAVS结合, 抑制TRIM25介导的MAVS的K48泛素化, 从而正向调控Ⅰ型干扰素反应[57]。
关于MAVS的去泛素化调控, 最新研究鉴定了一个与MAVS相互作用的OUT 家族成员OTUD4 (OTU deubiquitinase 4)[58]。在病毒感染时, OTUD4的表达受转录因子IRF3/7的调控增强, 与MAVS互作并消除MAVS的K48位多泛素链, 从而维持MAVS的稳定性, 促进宿主IFN抗病毒信号。反之, 敲除OTUD4削弱VSV病毒触发的IRF3和NF-κB的激活以及其下游靶基因的表达, 导致VSV复制增强[58]。OUT家族另外一个成员YOD1, 也能消除MAVS蛋白的K63位泛素化修饰, 抑制MAVS的聚集活化以及向下游的信号转导[59]。
鱼类MAVS的翻译后修饰调控 中国科学院水生生物研究所在鱼类MAVS介导的抗病毒免疫反应的泛素化修饰调控中作出了开创性的工作。pVHL (Protein von Hippel-Lindau) 作为VHL-延伸蛋白B/C E3连接酶复合物的组成部分, 以往的研究通常关注其在肿瘤抑制中的功能。利用斑马鱼模型敲除vhl基因发现: 在病毒感染后, 与野生型斑马鱼胚胎中低水平表达的MAVS相比, vhl基因敲除的斑马鱼胚胎的MAVS表达水平很高, 与敲除基因胚胎的强抗病毒能力直接相关[60]。机制研究发现, pVHL靶向MAVS的K420残基, 通过催化形成K48连接的聚泛素链, 引导MAVS通过蛋白酶体途径降解, 从而抑制斑马鱼的IFN抗病毒免疫反应[60]。研究人员在研究SVCV的免疫逃避中发现, SVCV病毒的N蛋白能促进MAVS的K48位泛素化修饰, 导致MAVS降解、抑制斑马鱼IFNφ1的产生, 从而达到免疫逃避的目的[61]。但是其中MAVS如何发生K48泛素化修饰的机制不清楚。
3.4 MITA/STING
哺乳类MITA蛋白的泛素化修饰调控 MITA(Mediator of IRF3 activation; 也称为STING, ERIS和MYPS)介导的IFN信号通路通常被认为由DNA病毒感染所触发, 而MAVS信号则由RNA病毒感染诱导。特异识别病毒DNA的模式识别受体(如cGAS等)激活的MITA信号同样能激活蛋白激酶TBK1, 进而激活IRF3介导IFN抗病毒免疫反应[1]。但是Ishikawa等[62]用RNA病毒VSV和SeV感染MITA基因敲除的MEFs细胞时发现, MITA缺陷也导致该两株RNA病毒触发的IFN抗病毒信号的减弱。因此, MITA可能在特定的细胞中, 对某些RNA病毒介导的Ⅰ型干扰素产生的信号通路也发挥作用[63]。
作为重要的接头蛋白, MITA的功能同样受到泛素化修饰的调控。Sev病毒感染促进E3 泛素连接酶 RNF5与MITA的互作, 并靶向MITA在K150位点发生K48泛素化链修饰, 引导MITA通过蛋白酶体途径降解、进而负调控宿主的抗病毒免疫反应[64]。TRIM家族成员TRIM29和TRIM30α与RNF5功能类似[65, 66]。而同为TRIM家族的TRIM32则催化MITA在K20/150/224/236位点处的K63泛素化修饰, 激活MITA信号通路[67]。TRIM56靶向MITA的K63连接泛素化修饰诱导MITA的二聚化, 进而激活下游TBK1-IFN信号[68]。此外, 内质网蛋白AMFR/INSIG1(Autocrine motility factor receptor/ insulin induced gene 1)复合体(一种E3 泛素连接酶复合体)能催化MITA发生K27位多聚泛素化, 促进TBK1的招募和活化[69]。值得一提的是, RNF26在K150上促进MITA的K11泛素化修饰, 而RNF5同样靶向MITA的K150位点促进K48连接的泛素化链修饰, 表明RNF26和RNF5的博弈可能协同调控了MITA介导的Ⅰ型干扰素表达[70]。
在MITA的去泛素化研究中, 发现USP18通过招募 USP20特异性消除MITA上缀合的K48多聚泛素链, 阻断MITA蛋白的降解途径, 从而促进天然抗病毒免疫反应[71]。另一个去泛素化酶USP13, 主要消除MITA蛋白上的K27连接的泛素化链修饰, 而不是K63或K2连接的多聚泛素化链[72]。因此, USP13实际上削弱了MITA对蛋白激酶TBK1招募。在HSV-1感染的细胞中, 去泛素化酶CYLD选择性地消除MITA蛋白的K48位泛素化链修饰稳定MITA蛋白[73], 而USP21 和USP49水解MITA蛋白的K63泛素化链[74, 75], 抑制MITA蛋白的激活。
鱼类MITA蛋白的泛素化修饰调控 有关鱼类MITA和MAVS的功能研究初步显示, 这两个接头蛋白在病毒感染的鱼类细胞中都能发挥促进IFN抗病毒免疫反应的功能。由于没有直接基因敲除实验加以验证, 现在还难以区分鱼类MITA和MAVS是否同哺乳类的同源基因一样, 分别在RNA病毒和DNA病毒感染诱发的信号通路中发挥作用[76, 77]。最近有报道, IHNV病毒的N蛋白靶向MITA导致MITA的泛素化降解, 尽管其中机制不清楚, 但是也表明鱼类MITA在抑制病毒感染中的重要作用[78]。另外, 在石斑鱼中鉴定了finTRIM家族基因如TRIM82能抑制MITA介导的抗病毒免疫反应, 但其中的分子机制不清楚[79]。同一个研究团队还发现石斑鱼TRIM35能抑制MAVS、MITA和TBK1介导的抗病毒免疫反应, 但是对MDA5的抗病毒免疫反应没有调控作用[80]。虽然TRIM家族蛋白的RING结构域可能赋予它们具有E3泛素连接酶活性, 但是石斑鱼TRIM82和TRIM35是否具有E3酶活性, E3酶活性是否与其负调控有关还有待更深入研究。
3.5 TBK1
哺乳类TBK1的泛素化修饰调控 TBK1(TANK binding kinase-1)最初被鉴定为与TANK(TRAF family member-associated NF-κB activator)相互作用的蛋白激酶。在RLR信号通路中, 活化的MAVS形成prion-like聚集物, 然后通过TRAF3招募TBK1和IKKi(IκB-Kinase-i, 又称为IKKε), 磷酸化激活转录因子IRF3和IRF7, 激活后的IRF3/7从细胞质进入细胞核结合在IFN基因启动子上, 启动IFN基因的转录[1, 45]。
研究表明, E3泛素连接酶RNF128和Nrdp1 (Neuregulin receptor degradation protein-1, 又称RNF41)都通过催化TBK1的K63泛素化来促进IFN抗病毒免疫[81, 82]。NLRP4(NLR family pyrin domain containing 4)则负调控Ⅰ型IFN反应, 机制是招募E3连接酶DTX4(Deltex E3 ubiquitin ligase 4)对底物TBK1通过K48泛素化靶向的蛋白酶体降解; 敲除DTX4基因降低TBK1蛋白K48泛素化修饰介导的降解, 增强TBK1和IRF3 的磷酸化激活[83]。同样, TRIP(TRAF-interacting protein)也通过介导TBK1的K48泛素化, 促进TBK1降解、从而负调控IFNβ的产生[84]。另外, 凝集素家族成员Siglec1(Sialic acid binding Ig-like lectin 1)抑制抗病毒免疫反应的机制是: 首先与DAP12(DNAX-activating protein of 12 kD;又称TYROBP, transmembrane immune signaling adaptor)互作以募集并激活SHP2(又称PTPN11, protein tyrosine phosphatase non-receptor type 11), 激活的SHP2再招募E3泛素连接酶 TRIM27, TRIM27靶向TBK1蛋白在K251和K372处发生K48泛素化作用促进TBK1 降解[85]。SOCS3(Suppressor of cytokine signaling 3)是一种IFN反应的负调控因子, 该蛋白与elongins B/C、cullin5和RBX-1一起构成E3泛素连接酶复合物。该复合物在与TBK1相互作用的过程中, SOCS3与TBK1结合并介导TBK1在K341和K344上的K48泛素化, 从而促进TBK1降解并抑制VSV和甲型流感病毒对IRF3的激活[86]。
TBK1去泛素化修饰研究发现, RNF11通过抑制TBK1的K63多聚泛素化修饰阻止抗病毒信号传导。TAX1BP[Tax1 (Human T cell leukemia virus type Ⅰ) binding protein 1]和锌指蛋白A20(Protein A20; 又称TNFAIP3, TNF alpha induced protein 3等)通过破坏TBK1和IKKε的K63连锁多聚泛素化作用终止抗病毒信号传导[87]。USP38特异性地消除TBK1在K670位氨基酸的K33泛素化修饰, 导致随后DTX4和TRIP在相同氨基酸位点的K48位泛素化修饰降解TBK1蛋白, 负调控IFN反应[88]。
鱼类TBK1的翻译后修饰调控 TBK1作为磷酸化转录因子激活IRF3/7的蛋白激酶, 常作为病毒抵御宿主免疫的靶标。SVCV编码的P蛋白能阻止TBK1对IRF3的磷酸化激活从而达到免疫逃避的目的[89]。还有研究发现GCRV感染体外培养细胞, 导致细胞TBK1蛋白的K63泛素化修饰减弱, K48泛素化修饰增强[90], 但是其中的分子机制还有待揭示。我们实验室在研究鱼类IFN反应的调控机制时, 从鲫中鉴定了一个物种特异的基因, 该基因的编码蛋白属于E3泛素连接酶家族TRIM家族, 并且与仅在鱼类中存在的一类TRIM亚家族finTRIM(fish novel TRIM)成员具有最高同源性, 因此命名为FTRCA1(finTRIM Carassius auratus 1)[15]。该基因在近源物种中如银鲫的基因组中都找不到直向同源基因(Ortholog), 但是表达调控分析表明, FTRCA1是一个典型的ISG, 表明其在鲫抗病毒免疫反应中发挥某种功能。实验证实FTRCA1具有E3泛素连接酶活性, 功能研究发现FTRCA1通过溶酶体自噬途径降解TBK1, 从而负调控病毒诱导宿主的IFN反应。过量表达FTRCA1没有增强TBK1的泛素化修饰程度, 但是缺失RING结构域影响FTRCA1负调控功能的发挥, 表明FTRCA1的E3活性在其负调控TBK1介导的抗病毒免疫反应中至关重要。虽然其中的机制还有待揭示, 但是, 由于FTRCA1是一个物种特异的finTRIM成员, 在其他鱼类中找不到一一对应的同源基因, 因此研究结果揭示了具有物种特异的鱼类干扰素反应的调控机制[15]。类似于哺乳类, 大黄鱼有E3泛素连接酶基因Nrdp1。尽管有证据显示Nrdp1能与大黄鱼TBK1发生互作, 但是缺乏后续的生理功能研究[91]。
3.6 IRF3/7
哺乳类IRF3/7的泛素化修饰调控 转录因子IRF3/7的磷酸化激活与机体天然抗病毒反应息息相关, 因此IRF3/7的磷酸化与泛素化修饰调控直接耦联。与IRF3直接作用的相关E3泛素连接酶蛋白, 如TRIM26在病毒感染的细胞中移位到核, 与核中的磷酸化IRF3蛋白结合并促进后者K48泛素化和降解[92]。HECT家族成员的RAUL具有K48位泛素化修饰IRF3/7、介导蛋白随后降解的功能[93]。RLR信号诱导的细胞凋亡是另外一种抗病毒途径, 其机制是转录因子IRF3被目前发现的唯一一个介导线性泛素链合成的E3泛素连接酶LUBAC介导发生线性化修饰, 被线性泛素链修饰的IRF3不参与诱导ISG的表达, 而诱导细胞凋亡相关基因的表达[94]。另外, 作用于MITA的蛋白RNF26虽然不能与IRF3直接互作, 也未能证实对IRF3有多聚泛素化修饰, 但实验证据显示RNF26能介导IRF3通过自噬溶酶体途径降解[70]。与IRF7直接作用的E3泛素连接酶蛋白, 目前有TRIM家族的TRIM8和TRIM28。TRIM8可以保护磷酸化激活的IRF7蛋白、避免通过蛋白酶体途径降解, 从而促进IRF7的功能 [95]。而TRIM28则介导IRF7蛋白的SUMOylation(SUMO是一种与泛素非常同源的小分子, 也类似泛素分子一样对底物蛋白进行多聚化链修饰, 称为SUMOylation, 是一种类泛素化修饰方式), 抑制IRF7蛋白的转录激活功能[96]。关于IRF3/7的去泛素化修饰, 最近一份报道显示: 在HSV-1和VSV感染的细胞中, OTUD1通过消除IRF3的K63位泛素化修饰, 抑制IRF3与下游基因启动子的结合, 负调控IFN反应[97]。
鱼类IRF3/7的泛素化修饰调控 中国科学院水生生物研究所在研究草鱼呼肠孤病毒GCRV与鱼类细胞互作机制时发现, GCRV病毒编码蛋白VP56可能通过K48泛素化修饰介导TBK1激活的IRF7蛋白的降解从而负调控IFN反应[98]。该研究团队在斑马鱼中也鉴定到两个负调控因子RPZ5 (Rapunzel 5)和NDRG1a (N-myc downstream-regulated gene 1a), 分别通过相似的机制, 促进磷酸化IRF7蛋白的K48泛素化修饰、然后经蛋白酶体途径降解、最后负调控IFN反应[99, 100]。这些研究揭示了GCRV感染鱼类细胞存在免疫逃避机制, 也表明鱼类细胞的IFN抗病毒免疫反应存在自身调控。此外, 鱼类也存在TRIM8基因, 同哺乳类同源基因一样, 过量表达大黄鱼TRIM8在体外能促进IRF3/7基因的表达水平, 同时促进ISRE启动子的活性[101]。需要指出的是, 在以上报道中, 无论是否存在鱼类IRF3/7的泛素化修饰, 其中的调控机制还有待更深入的研究。
4. 问题与展望
迄今为止, 大量的E3泛素连接酶和DUB被认为是重要的免疫调节剂, 通过介导RLR信号分子的泛素化修饰和去泛素化修饰来调控宿主的IFN抗病毒反应。综合分析近年来的相关研究可以发现, 针对K48位泛素化修饰和K63位泛素化修饰介导的蛋白降解和蛋白激活的研究较多, 其中的分子机制也较为清楚。但相比泛素化修饰密码的复杂性, 目前的机制研究仅揭示出冰山一角, 还有更多的泛素化修饰类型及它们介导的生理功能亟待发现。此外, 去泛素化相关的DUB的研究报道相对较少。
随着鱼类基因组数据及各种组学数据的增加, 鱼类基因的鉴定已经不再是制约功能研究的障碍。事实上, 近十年来鱼类干扰素抗病毒免疫分子的功能研究取得长足进展, 国内的研究水平已经处于世界前沿。不仅引领泛素化修饰的功能研究进展, 而且也涉足类泛素化修饰在抗病毒免疫反应中的调控研究, 如Neddylation[102]。但是相比哺乳类的研究深度和广度, 鱼类相关研究还刚刚起步, 还需要对揭示的功能表象开展更细致的机制研究。比如, 需要对参与泛素化修饰的相关酶进行直接鉴定, 还需要对泛素化类型和靶向氨基酸位点进行鉴定等。鱼类种类多, 导致研究对象分散, 不得不对同一基因在不同研究对象中重复开展工作, 间接滞后了研究的深度。其次, 虽然在研究报道中已经有体内实验证据出现[60, 102], 但是目前相关的研究还多利用体外培养细胞进行, 缺乏基因敲除实验的证据, 这些缺陷可能导致不同实验室取得不一致的结果, 如关于鱼类LGP2的功能研究就是一个典型例子。再次, 哺乳类相关的研究也是一个逐渐认识的过程, 如关于RIG-Ⅰ蛋白K63泛素化修饰激活的认识一直处于修正之中[20－23]。这提示鱼类方面的研究不仅是对哺乳类研究的一个补充和证实, 而且对于保守的E3酶基因和去泛素化酶基因的功能研究, 也可能揭示出不同于哺乳类的、而特异于鱼类的功能和作用机制。另外, 比较基因组学已经揭示出鱼类具有自身特有的一些基因, 如鱼类TRIM家族就有一个亚家族称为finTRIM, 该亚家族成员全部属于鱼类特有[103－105]。但是不同鱼类的finTRIM亚家族的成员也不尽相同, 表明很多基因可能是鱼类物种特异的基因。对这些基因的研究无疑将揭示出鱼类物种特异的抗病毒免疫反应调控机制[15]。最后, 虽然许多鱼类基因与哺乳类非常同源, 但是由于硬骨鱼类存在普遍的基因组加倍事件, 因此导致基因拷贝数与哺乳类相比有差异, 或者基因编码蛋白不完全类同。如在目前版本的斑马鱼基因组中注释的Riplet/RNF135蛋白与人Riplet/RNF135蛋白相比可能缺少了N端RING结构域。还比如TRIM家族成员之间序列同源性高, 而鱼类TRIM家族因为扩增导致基因拷贝数剧增, 因此出现命名困难以致混淆错误发生[15]。鉴于鱼类基因的命名多根据哺乳类同源基因来命名, 因此, 对鱼类基因的正确鉴定与正确命名以避免与哺乳类基因的功能认知出现混淆非常重要。
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图 1 鱼类和哺乳类RLR介导的抗病毒免疫反应的泛素化修饰调控
蓝色和红色箭头分别代表对RLR关键分子的正、负调控作用。深色椭圆及文字标明了泛素化和去泛素化的类型, 其中“+”和“−”分别表示对不同类型的泛素链的泛素化和去泛素化作用。根据所查阅的文献, 图中只列出了在相关调控方面研究较为清楚的RLR成员以及介导的(去)泛素化的调控机制
Figure 1. (De) ubiquitination-mediated regulation of antiviral immune RLR-signaling pathway in mammal and fish
The blue and red arrows in the figure represent the positive and negative regulatory effects on the key molecules of RLR signaling, respectively. Dark ellipses with text indicate the types of ubiquitin chains that are added to or removed from the targeted proteins (“+”: ubiquitination; “−”: deubiquitination). According to the literature consulted, only the RLR members with detailed regulatory mechanisms are listed
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