Rab7b和LAPF负向调控TLRs信号通路的效应与机制的研究
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摘要
第一部分晚期内体／溶酶体定位的小G蛋白Rab7b抑制巨噬细胞TLR9刺激产生的促炎性因子和Ⅰ型干扰素
大量研究证明,TLR9的异常活化参与了多种自身免疫性疾病如系统性红斑狼疮等的发病过程,。基于上述研究事实,TLR9拮抗剂有望成为这些自身免疫性疾病防治的潜在靶点。为此,必须对于TLR9受体介导的效应与相关信号转导机制了解清楚,同时,发现并鉴定TLR9信号通路新的负向调控因子也具有十分重要的意义。众所周知,TLR9被活化后最终将被转运到晚期内体／溶酶体中,但是对于TLR9在细胞中的这一重新定位过程到底有何生物学重要意义,目前还不十分清楚。Rab7b是本实验室从人树突状细胞cDNA文库中通过随机大规模测序得到的一个与Rab7高度同源的新型分子,因此命名为Rab7b。Rab7b是一类鸟苷三磷酸酶,其主要定位在细胞的晚期内体和溶酶体中。本实验室之前的研究表明,Rab7b通过促进TLR4的溶酶体途径降解以负向调节TLR4信号通路。在本研究中,我们发现在巨噬细胞中TLR9的交联可以通过ERK和p38途径有效地抑制Rab7b的表达。相反,晚期内体／溶酶体定位的Rab7b在细胞内可以与TLR9共定位在溶酶体相关膜蛋白1(LAMP1)阳性的细胞器室内,Rab7b对于MyD88以及其下游信号并不存在调控效应,但是当TLR9被活化后Rab7b通过直接促进TLR9本身的溶酶体途径降解的翻译后修饰下调TLR9在巨噬细胞中的表达。相应的,Rab7b抑制TLR9下游的MAPK和NF-κB等转录因子的活性进而负向调节TLR9诱导的TNF-α,IL-6等促炎性因子和IFN-β为代表的Ⅰ型干扰素的产生。本研究结果提示,Rab7b通过促进TLR9本身的降解从而抑制TLR9信号通路中多种信号分子和转录因子的活性,抑制由TLR9诱导的促炎性因子和Ⅰ型干扰素的产生。该结果对于进一步深入研究TLR9触发的生物效应与相关信号通路的调控机制提高了新的线索和实验基础。
第二部分凋亡诱导蛋白LAPF负向调控TLR3和TLR9介导的促炎性因子和Ⅰ型干扰素产生的效应与机制研究
TLRs家族受体根据各自不同的亚细胞定位可以分成细胞膜表面的TLRs和细胞内定位的TLRs两大类。TLRs成员的不同空间分布可能存在一种与它们空间定位相关的调控新模式,为TLRs信号调控的机制研究提供了新的方向。本实验之前我们从人树突状细胞cDNA文库中通过随机大规模测序发现了的溶酶体相关的包含PH和FYVE结构域的凋亡诱导蛋白LAPF并报道了其参与TNF-α诱导的肿瘤细胞凋亡过程。LAPF与细胞内定位的TLRs成员相近的亚细胞定位使我们考虑是否存在LAPF参与胞内定位TLRs信号调控的可能。结果发现,LAPF可以负向调控巨噬细胞中胞内定位的TLR3和TLR9的信号通路,但却不能调控细胞膜定位的TLR4信号通路。小鼠原代巨噬细胞中过表达LAPF可以抑制TLR3和TLR9介导的TNF-α,IL-6和IFN-β的产生,LAPF的这种负向调控效应部分依赖于其包含的PH结构域。不仅仅是细胞内定位的TLRs,胞内dsRNA识别受体RIG-I同样受到LAPF的调控。由RIG-I介导识别的仙台病毒感染巨噬细胞所产生的IFN-β也同样被LAPF所抑制。荧光差异双向凝胶电泳以及后续的蛋白质谱分析实验发现,过表达LAPF降低了细胞内Calmodulin的总蛋白表达量。Calmodulin是细胞内最重要的Ca2+结合蛋白,可以活化下游CamKII,而CaMKII在本实验室之前的工作中已经被证明是TLRs信号完全活化所必须的。此外,LAPF也可以通过其PH结构域与磷酸化的Akt相互结合从而促进Akt的磷酸化。Akt的活化可以磷酸化下游底物GSK-3位于N-末端的抑制性丝氨酸磷酸化位点,从而抑制GSK-3的活性。GSK-3活性被抑制后竞争性地削弱了NF-κB依赖的促炎性因子的产生。因此,与TLR3和TLR9有相同亚细胞定位的LAPF通过下调细胞内Calmodulin的表达量以及活化Akt/GSK-3信号通路从而负向调控TLR3／9介导的促炎性因子和Ⅰ型干扰素的产生。该部分研究结果为细胞内定位的TLR信号通路调控的分子机制的研究提供了新的认识。
PartⅠLate endosome/lysosome-localized Rab7b suppresses TLR9-initiated proinflammatory cytokine and typeⅠIFN production in macrophages and the underlying mechanisms
Inappropriate activation of TLR9 has been found to be involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. TLR9 antagonists have been proposed to be therapeutic for some kinds of autoimmune disease. However, new negative regulators of TLR9 signal pathway need to be identified, and the mechanisms for the control of TLR9 response need to be fully investigated. It is well known that TLR9 will be finally transported to late endosome/lysosome once activated; however, the exact mechanism and the biological significance of the subcellular redistribution have not been fully elucidated. Ras related in brain (Rab) 7b is a small guanosine triphosphatase, identified by us before, which is mainly localized in late endosome/lysosome. Our previous study shows that Rab7b can negatively regulate TLR4 signaling by promoting lysosomal degradation of TLR4. In this study, we show that TLR9 ligation can inhibit Rab7b expression in macrophages via ERK and p38 activation, In turn, the late endosome/lysosome-localized Rab7b can colocalize with TLR9 in lysosomal-associated membrane protein 1-positive compartment and down-regulate the expression of the TLR9 in macrophages by promoting TLR9 degradation once TLR9 is activated. Accordingly, Rab7b can negatively regulate TLR9-triggered production of TNF-a, IL-6, and IFN-βin macrophages by impairing activation of MAPKs and NF-κB pathways. Our results suggest that the late endosome/lysosome-localized Rab7b can down-regulate TLR9-triggered proinflammatory cytokine and type I IFN production by impairing TLR9 signaling via promotion of TLR9 degradation.
Part II Apoptosis-inducing protein LAPF negatively regulates TLR3-and TLR9-meidiated proinflammatroy cytokine and type I interferon production and the underlying mechanisms
According to the subcellular localizations, the Toll-like receptors (TLR) could be divided into two categories, cell surface TLRs and intracelluar TLRs. The spatial differences of TLRs might be regulated by a new pattern related with their subcellular localization, which would provide a new mechanism for regulation of TLRs-triggered inflammatory innate response. Lysosome-associated apoptosis-inducing protein containing the plechstrin homology (PH) and FYVE domains, LAPF, has been first identified by us and found to be involved in the TNF-a-induced apoptosis of turner cells. The similar subcellular localization of LAPF and intracellular TLRs made us look for the possibility that LAPF might involve in the regulation of these intracellular TLRs signaling. As expected, we discovered that LAPF could negative regulate TLR3-and TLR9-initiated signaling, but not the cell surface-located TLR4, in macrophages. Overexpression of LAPF in primary peritoneal macrophages attenuated TLR3-and TLR9-trigged TNF-a, IL-6 and IFN-βproductions, and such a downregulation was partially dependent on its PH domain. Not only the intracellular TLRs signaling but also the intracellular dsRNA sensor RIG-I signaling could be regulated by LAPF. Sendaivirus-induced IFN-βproduction in macrophages, which was already domenstrated that this virus is recoginized by RIG-I, was inhibited by LAPF.2-D fluorescent difference gel electrophoresis and sequential protein spectrum indicated that overexpression of LAPF would decrease the total protein level of calmodulin in the cytoplasm. Calmodulin is the most important Ca2+binding protein and activates downstream CaMKII which has been demonstrated as a positive regulator in TLRs signaling. In addition, LAPF associated with phospho-Akt via its PH domain and ficilitied Akt's phosphorylation. Activated Akt downstream phosphorylated the N-terminal Ser residues of GSK-3 which inhibited its activity. The inhibition of GSK-3 competitively attenuated the NF-κB-dependent proinflammatory cytokine production. Thus, LAPF, the protein with the same subcellular localization of intracellular TLR3 and TLR9, negatively regulates TLR3 and TLR9 signaling via downregulating the calmodulin expression and activating Akt/GSK-3 pathway.
大量研究证明,TLR9的异常活化参与了多种自身免疫性疾病如系统性红斑狼疮等的发病过程,。基于上述研究事实,TLR9拮抗剂有望成为这些自身免疫性疾病防治的潜在靶点。为此,必须对于TLR9受体介导的效应与相关信号转导机制了解清楚,同时,发现并鉴定TLR9信号通路新的负向调控因子也具有十分重要的意义。众所周知,TLR9被活化后最终将被转运到晚期内体／溶酶体中,但是对于TLR9在细胞中的这一重新定位过程到底有何生物学重要意义,目前还不十分清楚。Rab7b是本实验室从人树突状细胞cDNA文库中通过随机大规模测序得到的一个与Rab7高度同源的新型分子,因此命名为Rab7b。Rab7b是一类鸟苷三磷酸酶,其主要定位在细胞的晚期内体和溶酶体中。本实验室之前的研究表明,Rab7b通过促进TLR4的溶酶体途径降解以负向调节TLR4信号通路。在本研究中,我们发现在巨噬细胞中TLR9的交联可以通过ERK和p38途径有效地抑制Rab7b的表达。相反,晚期内体／溶酶体定位的Rab7b在细胞内可以与TLR9共定位在溶酶体相关膜蛋白1(LAMP1)阳性的细胞器室内,Rab7b对于MyD88以及其下游信号并不存在调控效应,但是当TLR9被活化后Rab7b通过直接促进TLR9本身的溶酶体途径降解的翻译后修饰下调TLR9在巨噬细胞中的表达。相应的,Rab7b抑制TLR9下游的MAPK和NF-κB等转录因子的活性进而负向调节TLR9诱导的TNF-α,IL-6等促炎性因子和IFN-β为代表的Ⅰ型干扰素的产生。本研究结果提示,Rab7b通过促进TLR9本身的降解从而抑制TLR9信号通路中多种信号分子和转录因子的活性,抑制由TLR9诱导的促炎性因子和Ⅰ型干扰素的产生。该结果对于进一步深入研究TLR9触发的生物效应与相关信号通路的调控机制提高了新的线索和实验基础。
第二部分凋亡诱导蛋白LAPF负向调控TLR3和TLR9介导的促炎性因子和Ⅰ型干扰素产生的效应与机制研究
TLRs家族受体根据各自不同的亚细胞定位可以分成细胞膜表面的TLRs和细胞内定位的TLRs两大类。TLRs成员的不同空间分布可能存在一种与它们空间定位相关的调控新模式,为TLRs信号调控的机制研究提供了新的方向。本实验之前我们从人树突状细胞cDNA文库中通过随机大规模测序发现了的溶酶体相关的包含PH和FYVE结构域的凋亡诱导蛋白LAPF并报道了其参与TNF-α诱导的肿瘤细胞凋亡过程。LAPF与细胞内定位的TLRs成员相近的亚细胞定位使我们考虑是否存在LAPF参与胞内定位TLRs信号调控的可能。结果发现,LAPF可以负向调控巨噬细胞中胞内定位的TLR3和TLR9的信号通路,但却不能调控细胞膜定位的TLR4信号通路。小鼠原代巨噬细胞中过表达LAPF可以抑制TLR3和TLR9介导的TNF-α,IL-6和IFN-β的产生,LAPF的这种负向调控效应部分依赖于其包含的PH结构域。不仅仅是细胞内定位的TLRs,胞内dsRNA识别受体RIG-I同样受到LAPF的调控。由RIG-I介导识别的仙台病毒感染巨噬细胞所产生的IFN-β也同样被LAPF所抑制。荧光差异双向凝胶电泳以及后续的蛋白质谱分析实验发现,过表达LAPF降低了细胞内Calmodulin的总蛋白表达量。Calmodulin是细胞内最重要的Ca2+结合蛋白,可以活化下游CamKII,而CaMKII在本实验室之前的工作中已经被证明是TLRs信号完全活化所必须的。此外,LAPF也可以通过其PH结构域与磷酸化的Akt相互结合从而促进Akt的磷酸化。Akt的活化可以磷酸化下游底物GSK-3位于N-末端的抑制性丝氨酸磷酸化位点,从而抑制GSK-3的活性。GSK-3活性被抑制后竞争性地削弱了NF-κB依赖的促炎性因子的产生。因此,与TLR3和TLR9有相同亚细胞定位的LAPF通过下调细胞内Calmodulin的表达量以及活化Akt/GSK-3信号通路从而负向调控TLR3／9介导的促炎性因子和Ⅰ型干扰素的产生。该部分研究结果为细胞内定位的TLR信号通路调控的分子机制的研究提供了新的认识。
PartⅠLate endosome/lysosome-localized Rab7b suppresses TLR9-initiated proinflammatory cytokine and typeⅠIFN production in macrophages and the underlying mechanisms
Inappropriate activation of TLR9 has been found to be involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. TLR9 antagonists have been proposed to be therapeutic for some kinds of autoimmune disease. However, new negative regulators of TLR9 signal pathway need to be identified, and the mechanisms for the control of TLR9 response need to be fully investigated. It is well known that TLR9 will be finally transported to late endosome/lysosome once activated; however, the exact mechanism and the biological significance of the subcellular redistribution have not been fully elucidated. Ras related in brain (Rab) 7b is a small guanosine triphosphatase, identified by us before, which is mainly localized in late endosome/lysosome. Our previous study shows that Rab7b can negatively regulate TLR4 signaling by promoting lysosomal degradation of TLR4. In this study, we show that TLR9 ligation can inhibit Rab7b expression in macrophages via ERK and p38 activation, In turn, the late endosome/lysosome-localized Rab7b can colocalize with TLR9 in lysosomal-associated membrane protein 1-positive compartment and down-regulate the expression of the TLR9 in macrophages by promoting TLR9 degradation once TLR9 is activated. Accordingly, Rab7b can negatively regulate TLR9-triggered production of TNF-a, IL-6, and IFN-βin macrophages by impairing activation of MAPKs and NF-κB pathways. Our results suggest that the late endosome/lysosome-localized Rab7b can down-regulate TLR9-triggered proinflammatory cytokine and type I IFN production by impairing TLR9 signaling via promotion of TLR9 degradation.
Part II Apoptosis-inducing protein LAPF negatively regulates TLR3-and TLR9-meidiated proinflammatroy cytokine and type I interferon production and the underlying mechanisms
According to the subcellular localizations, the Toll-like receptors (TLR) could be divided into two categories, cell surface TLRs and intracelluar TLRs. The spatial differences of TLRs might be regulated by a new pattern related with their subcellular localization, which would provide a new mechanism for regulation of TLRs-triggered inflammatory innate response. Lysosome-associated apoptosis-inducing protein containing the plechstrin homology (PH) and FYVE domains, LAPF, has been first identified by us and found to be involved in the TNF-a-induced apoptosis of turner cells. The similar subcellular localization of LAPF and intracellular TLRs made us look for the possibility that LAPF might involve in the regulation of these intracellular TLRs signaling. As expected, we discovered that LAPF could negative regulate TLR3-and TLR9-initiated signaling, but not the cell surface-located TLR4, in macrophages. Overexpression of LAPF in primary peritoneal macrophages attenuated TLR3-and TLR9-trigged TNF-a, IL-6 and IFN-βproductions, and such a downregulation was partially dependent on its PH domain. Not only the intracellular TLRs signaling but also the intracellular dsRNA sensor RIG-I signaling could be regulated by LAPF. Sendaivirus-induced IFN-βproduction in macrophages, which was already domenstrated that this virus is recoginized by RIG-I, was inhibited by LAPF.2-D fluorescent difference gel electrophoresis and sequential protein spectrum indicated that overexpression of LAPF would decrease the total protein level of calmodulin in the cytoplasm. Calmodulin is the most important Ca2+binding protein and activates downstream CaMKII which has been demonstrated as a positive regulator in TLRs signaling. In addition, LAPF associated with phospho-Akt via its PH domain and ficilitied Akt's phosphorylation. Activated Akt downstream phosphorylated the N-terminal Ser residues of GSK-3 which inhibited its activity. The inhibition of GSK-3 competitively attenuated the NF-κB-dependent proinflammatory cytokine production. Thus, LAPF, the protein with the same subcellular localization of intracellular TLR3 and TLR9, negatively regulates TLR3 and TLR9 signaling via downregulating the calmodulin expression and activating Akt/GSK-3 pathway.
引文
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