生物技术通报 ›› 2021, Vol. 37 ›› Issue (5): 197-211.doi: 10.13560/j.cnki.biotech.bull.1985.2020-1258
李凯晴1(
), 李莹2, 王艺磊3, 邹鹏飞3()
收稿日期:2020-10-12
出版日期:2021-05-26
发布日期:2021-06-11
作者简介:李凯晴,女,硕士研究生,研究方向：生态学;E-mail： 基金资助:
LI Kai-qing1(), LI Ying2, WANG Yi-lei3, ZOU Peng-fei3()
Received:2020-10-12
Published:2021-05-26
Online:2021-06-11
摘要：
受体相互作用蛋白（RIP）是介导细胞死亡信号和炎症反应的关键调节因子,在调节免疫反应和维持机体稳态方面起着至关重要的作用。RIP在哺乳动物中参与了细胞死亡、炎症反应、先天免疫等不同的生物学过程,而鱼类作为重要的脊椎动物类群,关于RIP在鱼类中的功能我们仍然所知有限。因此,主要综述了RIP家族成员的分子结构、介导的信号通路和作用机制,以及其在硬骨鱼类中的研究进展,旨为深入解析鱼类乃至哺乳动物的免疫反应和抗病机制奠定基础。
李凯晴, 李莹, 王艺磊, 邹鹏飞. 受体相互作用蛋白的功能及在硬骨鱼类中的研究进展[J]. 生物技术通报, 2021, 37(5): 197-211.
LI Kai-qing, LI Ying, WANG Yi-lei, ZOU Peng-fei. The Function of Receptor-interacting Protein（RIP）Kinases and the Research Progress in Teleost Fish[J]. Biotechnology Bulletin, 2021, 37(5): 197-211.
图1 哺乳动物 RIP 家族成员及蛋白结构域示意图 KD（kinase domain,激酶结构域）;RHIM（receptor-interacting-protein homotypic interaction motif,RIP同源相互作用基序）;DD（death domain,死亡结构域）;CARD（caspase activation and recruitment domain,天冬氨酸半胱氨酸蛋白酶激活募集域）;ANK（ankyrin repeat,锚蛋白重复序列）;Roc/CoR结构域（ras complex protein/C-terminal of Roc）;LRR（leucine-rich repeat,富亮氨酸重复序列）
Fig. 1 Protein domain of mammalian RIP family members KD stands for kinase domain, RHIM stands for receptor-interacting-protein homotypic interaction motif, DD stands for death domain, CARD stands for caspase activation and recruitment domain, ANK stands for ankyrin repeat, Roc/CoR stands for ras complex protein/C-terminal of Roc, LRR leucine-rich repeat
图2 哺乳动物 RIP1 和 RIP3 介导的信号通路 TNF-α与其受体TNFR1结合后,通过接头蛋白TRADD募集RIP1,激活NF-κB信号通路介导炎症反应,也可启动caspase依赖性细胞凋亡。TLR3和TLR4分别识别dsRNA和LPS,通过接头分子TRIF招募RIP1,RIP1可以与TRIF、TRAF6等结合介导下游NF-κB信号的激活从而诱导促炎细胞因子的转录;RIP1与FADD和caspase-8结合形成死亡复合物介导细胞凋亡;在caspase-8活性受到抑制时,可通过RIP1-RIP3-MLKL坏死小体的组装介导细胞程序性坏死,RIP3可以激活炎症小体介导细胞焦亡。脂多糖（lipopolysaccharide,LPS）;肿瘤坏死因子-α（tumor necrosis factor alpha,TNF-α）;肿瘤坏死因子受体1（TNF-receptor 1,TNFR1）;肿瘤坏死因子受体相关死亡域蛋白（TNF-receptor-associated death domain,TRADD）;肿瘤坏死因子受体相关因子（TNF receptor associated factor,TRAF）;凋亡抑制蛋白（cellular inhibitor of apoptosis proteins,cIAPs）;死亡结构域蛋白（Fas-associated death domain,FADD）;核转录因子-κB（nuclear transcription factor-κB,NF-κB）;Toll样受体（toll-like receptor,TLR）;β干扰素TIR结构域接头蛋白相关接头分子（TIR domain-containing adaptor-inducing IFNβ-related adaptor molecule,TRAM）;β干扰素TIR结构域接头蛋白（TIR domain-containing adaptor-inducing IFNβ,TRIF）; NOD样受体家族含吡啶结构域蛋白3（NOD-like receptor family pyrin domain containing 3,NLRP3）;凋亡相关斑点样蛋白（apoptosis-associated speck-like protein containing CARD,ASC）;白介素-1（Interleukin-1,IL-1）
Fig. 2 RIP1 and RIP3-mediated signaling pathways in mammals RIP1 is recruited via the adaptor protein TRADD to the TNFR1 upon the stimulation of TNF-α, and then activates NF-κB signaling pathway to mediate inflammation and initiates caspase-dependent cell apoptosis. The dsRNA and LPS could be recognized by TLR3 and TLR4, respectively, which then recruit the adaptor molecule TRIF to interact with RIP1, and then associate with TRAF6 to participate in the activation of downstream NF-κB signals, thereby inducing the transcription of pro-inflammatory cytokines. RIP1 mediates cell apoptosis by binding to FADD and caspase-8 to form a death complex. When the activity of caspase-8 is inhibited, the assembly of RIP1-RIP3-MLKL necrosomes mediates cell necrosis, and then RIP3 activates inflammasomes to mediate cell pyrotosis. LPS stands for Lipopolysaccharide. TNF-α stands for Tumor necrosis factor alpha. TNFR1 stands for TNF-receptor 1. TRADD stands for TNF-receptor-associated death domain. TRAF stands for TNF receptor associated factor. cIAPs stands for Cellular inhibitor of apoptosis proteins. FADD stands for Fas-associated death domain. NF-κB stands for Nuclear transcription factor-κB. TLR stands for Toll-like receptor. TRAM stands for TIR domain-containing adaptor-inducing IFNβ-related adaptor molecule. TRIF stands for TIR domain-containing adaptor-inducing IFNβ. NLRP3 stands for NOD-like receptor family pyrin domain containing 3. ASC stands for Apoptosis-associated speck-like protein containing CARD. IL-1 stands for Interleukin-1
图3 哺乳动物 RIP2 介导的信号通路 NNOD1和NOD2分别识别病原菌iE-DAP和MDP,招募并激活下游RIP2,从而活化TAB-TAK和IKK复合体并诱导NF-κB和MAPK信号通路激活;TRIP6和RIP7正调控NOD1/2-RIP2介导的信号通路,caspase-12、A20、OTULIN和CYLD负调控NOD1/2-RIP2介导的信号通路;RIP2也可与caspase-1相互作用介导NF-κB的激活,而ASC可与RIP2竞争caspase-1抑制其对NF-κB的激活,促进促炎细胞因子的加工。iE-DAP（γ-d-glutamyl-meso-diaminopimelic acid, γ-d-谷氨酰-间二氨基丙酸）;MDP（muramyl dipeptide,胞壁酰二肽）;NOD（nucleotide-binding oligomerization domains,核苷酸结合寡聚化结构域蛋白）;XIAP（X-linked inhibitor of apoptosis protein,X连锁凋亡抑制蛋白）;TRIP6（thyroid hormone receptor interactor 6,甲状腺激素受体相互作用蛋白6）;CYLD（cylindromatosis,头帕肿瘤综合征蛋白）;TAK（TGFβ-activated kinase,转化生长因子激酶）;TAB（TGFβ-activated kinase binding protein,转化生长因子激酶靶蛋白）;IKK（inhibitor of nuclear factor kappa-B kinase,IκB激酶）;MAPK（mitogen-activated protein kinase,促分裂原活化蛋白激酶）
Fig. 3 RIP2-mediated signaling pathways in mammals RIP2 is recruited and activated by NOD1 and NOD2, which recognize iE-DAP and MDP, respectively, thereby activating TAB-TAK and IKK complexes and inducing activation of NF-κB and MAPK signaling pathways. TRIP6 and RIP7 positively regulate NOD1/2-RIP2 mediated signaling pathway, whereas caspase-12, A20, OTULIN and CYLD negatively regulate the NOD1/2-RIP2 mediated signaling pathway. RIP2 can interact with caspase-1 to mediate the activation of NF-κB, whereas ASC competes with RIP2 to inhibit the activation of NF-κB by caspase-1 and promotes the processing of proinflammatory cytokines. iE-DAP stands for γ-d-glutamyl-meso-diaminopimelic acid. MDP stands for muramyl dipeptide. NOD stands for nucleotide-binding oligomerization domains. XIAP stands for X-linked inhibitor of apoptosis protein. TRIP6 stands for thyroid hormone receptor interactor 6. CYLD stands for cylindromatosis. TAK stands for TGFβ-activated kinase. TAB stands for TGFβ-activated kinase binding protein. IKK stands for inhibitor of nuclear factor kappa-B kinase. and MAPK stands for mitogen-activated protein kinase
图4 硬骨鱼类 RIP1、RIP2 和 RIP3 介导的信号通路 硬骨鱼类RIP1通过与TRIF相互作用参与TLR3、TLR19和TLR22介导的NF-κB信号通路的激活,与下游TRAF3结合活化TBK1和IKKε介导IFN的激活;RIG-I和MDA5识别病毒dsRNA,通过接头分子MAVS介导下游IRF3和IRF7信号转导,而RIP1可负调控MAVS介导的RLRs抗病毒信号通路;在TNF-α的刺激下,RIP1、TRADD和TRAF2结合激活NF-κB信号通路,也可介导细胞凋亡;RIP1可与RIP3和MLKL形成坏死小体诱导细胞程序性坏死。RIP2与NOD1/2相互作用活化TAB-TAK1和IKK复合体并诱导NF-κB信号通路激活,促进促炎细胞因子产生;RIP2可参与MHC抗原呈递和自噬过程。RIG-Ⅰ（retinoic acid-inducible gene Ⅰ,维甲酸诱导基因蛋白Ⅰ）;MDA5（melanoma differentiation associated gene 5,黑色素瘤分化相关基因5）;MAVS（mitochondrial antiviral-signaling protein,线粒体抗病毒信号蛋白）;MHC（major histocompatibility complex,主要组织相容性复合体）;TBK1（TANK binding kinase 1,TANK结合激酶1）;IRF3（interferon regulatory factor 3,干扰素调节因子3）;IRF7（interferon regulatory factor 7,干扰素调节因子7）;ISGs（interferon stimulated genes,干扰素诱导基因）
Fig. 4 RIP1, RIP2, and RIP3-mediated signaling pathways in teleosts RIP1 is involved in activation of TLR3, TLR19, and TLR22 mediated NF-κB signaling pathway through interaction with TRIF, and also activates TBK1 and IKKε-mediated production of IFN by binding to downstream TRAF3 in teleosts. Recognition of viral dsRNA activates RIG-I and MDA5, which then mediate downstream IRF3 and IRF7 signal transduction through the adaptor molecule MAVS, whereas RIP1 negatively regulates MAVS-mediated RLRs antiviral signal pathway. The combination of RIP1, TRAD and TRAF2 activates NF-κB signaling pathway and mediates cell apoptosis upon the stimulation of TNF-α. RIP1 form necrosomes with RIP3 and MLKL to induce cell necrosis. RIP2 interacts with NOD1/2 to activate the TAB-TAK1 and IKK complexes and induce the activation of the NF-κB signaling pathway to promote the production of proinflammatory cytokines. RIP2 is involved in MHC antigen presentation and autophagy. RIG-Ⅰstands for retinoic acid-inducible geneⅠ. MDA5 stands for melanoma differentiation associated gene 5. MAVS stands for mitochondrial antiviral-signaling protein. MHC stands for major histocompatibility complex. TBK1 stands for TANK binding kinase 1. IRF3 stands for interferon regulatory factor 3. IRF7 stands for interferon regulatory factor 7. and ISGs stands for interferon stimulated genes
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