接头蛋白Gab1通过PI3K途径促进TLRs和RIG-I介导的天然免疫反应
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摘要
天然免疫反应是机体的第一道防线,时刻应对病原体的入侵,包括对于最初入侵的病毒、细菌保守组分的识别等等,以及后续的对于继发性免疫反应的活化与调控。而模式识别受体(Pattern-recognition receptors,PRRs)在机体监测入侵的病毒和细菌组分并启动天然免疫反应的过程中发挥了极其重要的作用。其中,Toll样受体(TLRs)和维甲酸诱导基因Ⅰ(RIG-Ⅰ)样螺旋酶在细胞产生Ⅰ型干扰素(Interferon,IFN)和促炎性细胞因子、清除病原体的作用过程中起到了必不可少的作用。然而,促进TLRs和RIG-Ⅰ介导的天然免疫反应充分活化的机制尚未十分清楚,还有待进一步深入研究。
Grb2相关结合蛋白1(Grb2-associated binder 1,Gab1)是一个脚手架/接头蛋白,主要参与膜表面受体酪氨酸激酶和非受体酪氨酸激酶的信号传递过程,包括生长因子类受体、细胞因子类受体、T/B细胞受体、Fc受体等等介导的信号转导过程。Gab1在TLRs或RIG-Ⅰ等介导的天然免疫反应过程中的作用,尚未见报道。在本研究中,我们发现Gab1参与TLRs和RIG-Ⅰ介导的信号通路,促进天然免疫反应的充分活化,起到一个信号放大的作用。
首先我们观察到了在巨噬细胞中Gab1显著促进了TLR4-、TLR3-and RIG-Ⅰ介导的interleukin-6(IL-6)、IL-1βand IFN-α/β的产生。小鼠原代腹腔巨噬细胞内Gab1特异性的siRNA干扰或者Gab1基因缺陷的小鼠成纤维细胞经TLR4-、TLR3-andRIG-Ⅰ介导的interleukin-6(IL-6)、IL-1βand IFN-α/β的产生显著降低;而稳定过表达Gab1的巨噬细胞经TLR诱导的上述促炎性细胞因子和Ⅰ型干扰素的表达则显著升高。相一致的是,Gab1基因缺陷减少了水泡性口炎病毒(VSV)感染诱导的IFN-α/β,以及IFN诱导基因IP-10和RANTES的产生。
除了促进MyD88依赖和TRIF依赖的MAPKs和NF-κB途径的活化以外,在TLRs和RIG-Ⅰ信号通路中,Gab1通过直接结合PI3K的p85亚基,促进PI3K/Akt活性。阻断PI3K/Akt通路减少了Gab1上调的IL-6和IFN-β产生。因此,在TLR4-、TLR3- andRIG-Ⅰ介导的天然免疫反应过程中,Gab1通过促进PI3K/Akt、MAPKs和NF-κB的活性,促进了信号通路的充分活化。Gab1在小鼠腹腔巨噬细胞是组成性高表达的,而在TLR4活化后Gab1发生迅速而持续性的表达下调。Gab1的这种表达下调模式可能是机体的一种自我保护性机制,防止过度炎症反应带来的损伤作用。
本研究首次发现了Gab1在天然免疫反应中的作用,发现Gab1除了促进TLRs介导的天然免疫反应以外,还促进了病毒感染引起的天然免疫反应,该研究结果进一步丰富了对于天然免疫反应的调控及其信号传导机制的认识。
Toll-like receptors(TLRs) and retinoic acid-inducible gene I(RIG-I)-like helicases are critical in the induction of type I interferon(IFNs) and proinflammatory cytokines to initiate innate immunity against invading pathogens.However,the mechanisms for the full activation of TLR and RIG-I-triggered innate response remain to be fully investigated.Grb2-associated binder 1(Gab1),a member of scaffolding/adaptor proteins, can mediate signal transduction from many receptors,however,whether and how Gab1 is required for TLR and RIG-I-triggered innate responses remains unknown.Here we demonstrated that Gab1 significantly enhanced TLR4-,TLR3- and RIG-I-triggered interleukin-6(IL-6),IL-1βand IFN-α/βproduction in macrophages.Gab1 knockdown in primary macrophages or Gabl deficiency in mouse embryonic fibroblasts significantly suppressed TLR4-,TLR3- and RIG-I-triggered production of IL-6,IL-1βand IFN-α/β.Consistently,Gab1 deficiency impaired vesicular stomatitis virus(VSV) infection-induced IFN-α/βproduction,thus leading to the increased VSV replication.In addition to promoting both MyD88- and TRIF-dependent MAPKs and NF-κB activation,Gab1 enhanced PI3K/Akt activation by directly binding p85 in TLR signaling and VSV infection.Blockade of PBK/Akt pathway attenuated Gab1-induced IL-6 and IFN-βproduction.Therefore,Gabl is needed for full activation of TLR4, TLR3 and RIG-I-triggered innate responses by promoting activation of PI3K/Akt, MAPKs and NF-κB pathways.Gab1 is constitutively highly expressed in macrophages and its expression is rapidly down-regulated by TLR4 activation,and such downregulation of Gab1 might be a protective mechanism to avoid excess inflammatory response.
Grb2相关结合蛋白1(Grb2-associated binder 1,Gab1)是一个脚手架/接头蛋白,主要参与膜表面受体酪氨酸激酶和非受体酪氨酸激酶的信号传递过程,包括生长因子类受体、细胞因子类受体、T/B细胞受体、Fc受体等等介导的信号转导过程。Gab1在TLRs或RIG-Ⅰ等介导的天然免疫反应过程中的作用,尚未见报道。在本研究中,我们发现Gab1参与TLRs和RIG-Ⅰ介导的信号通路,促进天然免疫反应的充分活化,起到一个信号放大的作用。
首先我们观察到了在巨噬细胞中Gab1显著促进了TLR4-、TLR3-and RIG-Ⅰ介导的interleukin-6(IL-6)、IL-1βand IFN-α/β的产生。小鼠原代腹腔巨噬细胞内Gab1特异性的siRNA干扰或者Gab1基因缺陷的小鼠成纤维细胞经TLR4-、TLR3-andRIG-Ⅰ介导的interleukin-6(IL-6)、IL-1βand IFN-α/β的产生显著降低;而稳定过表达Gab1的巨噬细胞经TLR诱导的上述促炎性细胞因子和Ⅰ型干扰素的表达则显著升高。相一致的是,Gab1基因缺陷减少了水泡性口炎病毒(VSV)感染诱导的IFN-α/β,以及IFN诱导基因IP-10和RANTES的产生。
除了促进MyD88依赖和TRIF依赖的MAPKs和NF-κB途径的活化以外,在TLRs和RIG-Ⅰ信号通路中,Gab1通过直接结合PI3K的p85亚基,促进PI3K/Akt活性。阻断PI3K/Akt通路减少了Gab1上调的IL-6和IFN-β产生。因此,在TLR4-、TLR3- andRIG-Ⅰ介导的天然免疫反应过程中,Gab1通过促进PI3K/Akt、MAPKs和NF-κB的活性,促进了信号通路的充分活化。Gab1在小鼠腹腔巨噬细胞是组成性高表达的,而在TLR4活化后Gab1发生迅速而持续性的表达下调。Gab1的这种表达下调模式可能是机体的一种自我保护性机制,防止过度炎症反应带来的损伤作用。
本研究首次发现了Gab1在天然免疫反应中的作用,发现Gab1除了促进TLRs介导的天然免疫反应以外,还促进了病毒感染引起的天然免疫反应,该研究结果进一步丰富了对于天然免疫反应的调控及其信号传导机制的认识。
Toll-like receptors(TLRs) and retinoic acid-inducible gene I(RIG-I)-like helicases are critical in the induction of type I interferon(IFNs) and proinflammatory cytokines to initiate innate immunity against invading pathogens.However,the mechanisms for the full activation of TLR and RIG-I-triggered innate response remain to be fully investigated.Grb2-associated binder 1(Gab1),a member of scaffolding/adaptor proteins, can mediate signal transduction from many receptors,however,whether and how Gab1 is required for TLR and RIG-I-triggered innate responses remains unknown.Here we demonstrated that Gab1 significantly enhanced TLR4-,TLR3- and RIG-I-triggered interleukin-6(IL-6),IL-1βand IFN-α/βproduction in macrophages.Gab1 knockdown in primary macrophages or Gabl deficiency in mouse embryonic fibroblasts significantly suppressed TLR4-,TLR3- and RIG-I-triggered production of IL-6,IL-1βand IFN-α/β.Consistently,Gab1 deficiency impaired vesicular stomatitis virus(VSV) infection-induced IFN-α/βproduction,thus leading to the increased VSV replication.In addition to promoting both MyD88- and TRIF-dependent MAPKs and NF-κB activation,Gab1 enhanced PI3K/Akt activation by directly binding p85 in TLR signaling and VSV infection.Blockade of PBK/Akt pathway attenuated Gab1-induced IL-6 and IFN-βproduction.Therefore,Gabl is needed for full activation of TLR4, TLR3 and RIG-I-triggered innate responses by promoting activation of PI3K/Akt, MAPKs and NF-κB pathways.Gab1 is constitutively highly expressed in macrophages and its expression is rapidly down-regulated by TLR4 activation,and such downregulation of Gab1 might be a protective mechanism to avoid excess inflammatory response.
引文
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