蛋白激酶Stk38在抗病毒固有免疫反应中的作用机制研究
发布时间：2018-07-31 18:03
【摘要】：固有免疫(innate immunity)又称天然免疫(natural immunity),是机体本身具有的抵抗外来病原体入侵的防御能力。固有免疫应答由模式识别受体(Pattern recognition receptors,PRRs)对病原体中的相对保守成分的识别而启动。这些病原体中相对保守的成分被称为病原相关分子模式(Pathogen associated molecular Patterns,PAMPs),在病原体生存或致病过程中所必须。模式识别受体识别相应的配体之后,能够通过激活下游的信号分子,经一系列信号转导过程,引起炎症细胞因子和Ⅰ型干扰素等免疫介质的分泌,促进机体进行免疫应答反应。对病毒成分的识别和应答是固有免疫反应的重要组成部分。对病毒核酸成分的识别主要通过TLRs、RLRs和病毒双链DNA识别分子进行。TLRs是一类膜受体家族,其中TLR3、TLR7和TLR8存在于细胞内体膜上,可以识别内体中的病毒成分。病毒被吞噬之后,其核酸成分就会暴露在吞噬细胞的内体中,与相应配体结合后TLRs能够分别通过接头蛋白TRIF或MyD88,经下游信号转导分子,活化IRF3、IRF7和NF-κB,促进Ⅰ型干扰素和炎症细胞因子的分泌。RLRs主要负责对胞浆中病毒RNA成分的识别,包括RIG-I和MDA-5两种受体。病毒感染细胞后核酸成分进入胞浆,被RLRs识别。RLRs完成识别后活化,并招募接头分子MAVS,进一步激活下游的信号通路,磷酸化IRF3、IRF7和NF-κB,诱导Ⅰ型干扰素和炎症细胞因子产生。已发现的病毒双链DNA识别分子众多,主要通过接头蛋白STING激活下游的信号通路,磷酸化IRF3、IRF7和NF-κB,诱导Ⅰ型干扰素和炎症细胞因子产生。细胞分泌的Ⅰ型干扰素可以通过自分泌或旁分泌的方式与细胞膜上的Ⅰ型干扰素受体结合,活化与之偶联的酪氨酸蛋白激酶Jak1(Janus kinase 1)和Tyk2(tyrosine kinase 2),经Jak-STAT信号通路,激活下游大量干扰素诱导基因(IFN-stimulated genes,ISGs)的转录。从而增强机体抗病毒能力,同时还可以再作用于模式识别信号通路,进一步促进Ⅰ型干扰素的产生,通过正反馈作用使细胞短时间产生足量Ⅰ型干扰素。而其中STAT1分子在该通路的活化中有重要作用。除受到上游干扰素信号的激活外,STAT1还可以在RIG-I活化后,经MAVS非依赖的信号直接磷酸化激活,发挥作用。由以上Ⅰ型干扰素分泌的信号网络的复杂性可以看出,对Ⅰ型干扰素分泌的调控也是一个十分复杂的体系。Ⅰ型干扰素分泌的调控机制一直是固有免疫领域研究的热点问题,对其深入研究也有利于我们更好地了解抗病毒固有免疫应答机制,并寻找感染性疾病的潜在治疗策略。丝氨酸/苏氨酸蛋白激酶38(Serine/threoninekinase38,Stk38),是NDR蛋白激酶家族的成员。其作为一种新型的Hippo信号通路蛋白激酶,在细胞生命活动中有广泛的生物学功能。我们通过前期研究发现,Stk38分子可以促进Smurf1介导的MEKK2的泛素化降解,负向调控TLR9介导的炎症反应,参与固有免疫应答。但其在抗病毒固有免疫领域是否有调控作用尚未见报道。本研究通过以下三个部分的内容,对以Stk38为代表的Hippo信号通路分子在抗病毒固有免疫应答中的调控机制展开研究。一、蛋白激酶Stk38对VSV诱导的巨噬细胞中IFN-β的表达调控作用本部分我们主要通过实验探究Stk38分子对抗病毒固有免疫反应是否有调控作用。利用小干扰RNA技术,在小鼠原代腹腔巨噬细胞中转染特异性靶向Stk38分子的siRNA后,通过实时荧光定量pcr检测IFN-βmRNA表达水平,ELISA检测细胞上清中IFN-β的含量,我们发现VSV感染诱导的IFN-β的产生能力明显下降。类似地,在stk38基因敲除小鼠腹腔巨噬细胞中也发现,VSV感染后其IFN-β的产生能力严重受损。另一方面,我们通过药物筛选获得稳定表达外源性stk38分子的raw264.7细胞株,与对照细胞株相比,VSV感染后,stk38高表达细胞株IFN-β的分泌水平相应升高。另外,我们还利用实时荧光定量PCR技术检测了VSV感染后Stk38基因敲除小鼠腹腔巨噬细胞中VSV病毒的核酸成分。结果发现,与对照细胞相比,stk38缺陷细胞中病毒的核酸拷贝数增高,复制能力更强。我们还在stk38缺陷小鼠体内建立了VSV急性感染疾病模型。通过检测小鼠血清中IFN-β的分泌水平我们发现,急性VSV感染后,缺陷小鼠血清中IFN-β的分泌明显减少。同时,Stk38缺陷小鼠的生存率也低于同窝对照野生型小鼠。通过以上实验结果我们证实,Stk38对VSV诱导的巨噬细胞IFN-β的分泌具有正向调控作用,并能够抑制病毒的增殖,同时在体内对病毒感染小鼠也具有保护作用。二、Hippo信号效应分子YAP对VSV诱导的巨噬细胞中IFN-β的表达调控作用由于Stk38是Hippo信号通路的调节分子,因此本部分我们为了发现Stk38对IFN-β分泌的调控机制,设计实验探究Hippo通路的效应分子yap是否参与Stk38对IFN-β的表达调控作用。在小鼠腹腔巨噬细胞中stk38缺失导致YAP表达水平增高。但是转染yap分子的siRNA对细胞表达IFN-β的能力没有影响,显示YAP对IFN-β不存在调控作用。以上实验结果表明,Stk38分子对IFN-β的调控是通过YAP非依赖的方式进行的。三、Stk38分子调控VSV诱导的IFN-β表达的分子机制本部分主要内容为Stk38调控IFN-β表达的具体分子机制相关的实验结果。我们通过对干扰素相关信号通路活化情况的筛选发现,VSV感染诱导的Stk38缺陷细胞中干扰素相关通路信号分子STAT1的磷酸化水平降低,提示Stk38可能通过调节STAT1的活化水平调控IFN-β的产生。通过文献回顾寻找线索,我们发现糖原合酶激酶3(GSK3)分子对STAT1的活化具有正向调控作用。因此我们利用GSK3分子的小干扰RNA或特异性抑制剂CHIR-99021处理细胞,发现对GSK3分子的抑制确实能够降低VSV诱导的STAT1的活化和IFN-β的表达。同时,在HEK293细胞中转染相关分子的高表达载体,我们发现Stk38分子可以与GSK3分子结合,通过阻断Akt对GSK3磷酸化修饰的机制,对GSK3的活性起到保护作用。最后,CHIR-99021能够阻断Stk38分子对STAT1活化和IFN-β表达的促进作用。我们通过本部分实验,初步证明Stk38可以通过调节GSK3-STAT1信号,促进VSV感染诱导的IFN-β的合成和分泌。综上所述,我们通过实验证实,Hippo信号通路新型蛋白激酶Stk38可以通过GSK3-STAT1信号途径,促进VSV感染诱导的IFN-β的合成和分泌。我们的研究首次发现Stk38分子在抗病毒固有免疫应答中具有调控作用,并初步探讨了其作用机制,提出Stk38分子能够通过与GSK3分子的相互作用,并经GSK3-STAT1信号促进IFN-β分泌,增强机体抗病毒的能力。对Stk38调控IFN-β分泌机制的发现,一方面进一步丰富了Stk38的生物学作用,使对该分子的功能有了新的认识;另一方面也对抗病毒固有免疫应答调控的信号网络有了部分拓展,为IFN-β分泌的调控机制研究提供了新的思路;另外,为病毒感染性疾病的治疗提供了一个潜在的新靶点。
[Abstract]:Innate immunity, also known as the natural immune (natural immunity), is the body's own defense ability to resist the invasion of foreign pathogens. The intrinsic immune response is initiated by the recognition of the Pattern recognition receptors (PRRs) on the relative conservatives in the pathogen. These pathogens are relatively conservative. Pathogen associated molecular Patterns (PAMPs), which is known as the pathogen associated molecular model (PAMPs), is necessary in the survival or pathogenesis of the pathogen. After the pattern recognition receptor recognizes the corresponding ligand, it can activate the downstream signal molecules through a series of signal transduction pathways, causing inflammatory cytokines and type I interferon and other immunization. The secretion of the medium promotes the body's immune response. Identification and response to the virus components are an important part of the inherent immune response. The identification of viral nucleic acids is mainly through the TLRs, RLRs and viral double stranded DNA recognition molecules that are a class of membrane receptor families, and TLR3, TLR7 and TLR8 exist on the intracellular membrane of the virus. To identify the virus components in the internal body. After the virus is phagocyted, its nucleic acid components will be exposed to the phagocytic inner body. After binding to the corresponding ligand, TLRs can transmit molecules through the joint protein TRIF or MyD88 respectively through the downstream signal transduction molecules, activating IRF3, IRF7 and NF- kappa B, promoting the secretion of.RLRs mainly by type I interferon and inflammatory cytokines. Responsible for identifying the RNA components of the cytoplasm of the cytoplasm, including two receptors of RIG-I and MDA-5. After the virus infected cells, the nucleic acid components entered the cytoplasm, activated by the RLRs recognition.RLRs, and recruited the joint molecule MAVS, further activating the downstream signal pathway, phosphorylated IRF3, IRF7, and NF- kappa B, inducing type I interferon and inflammatory cytokine production. The virus double stranded DNA recognition molecules are numerous, mainly through the joint protein STING activating the downstream signal pathway, phosphorylated IRF3, IRF7 and NF- kappa B, inducing type I interferon and inflammatory cytokine production. Activation and activation of tyrosine protein kinase Jak1 (Janus kinase 1) and Tyk2 (tyrosine kinase 2) activate the transcription of a large number of interferon induced genes (IFN-stimulated genes, ISGs) downstream by Jak-STAT signaling pathway, thereby enhancing the body's anti-virus ability and also reacting on the pattern recognition signaling pathway to further promote I The production of type IFN interferon produces a full amount of interferon I in short time by positive feedback, and the STAT1 molecule plays an important role in the activation of this pathway. In addition to the activation of the upstream interferon signal, STAT1 can also be activated directly by the MAVS non dependent signal after activation of RIG-I. The complexity of the interferon signaling network shows that the regulation of the type I interferon secretion is also a very complex system. The regulatory mechanism of type I interferon is a hot issue in the field of inherent immunity. It is also helpful for us to better understand the mechanism of antiviral inherent immune response and to find out the mechanism of antiviral innate immune response. The potential treatment strategy for finding infectious diseases. Serine / threonine protein kinase 38 (Serine/threoninekinase38, Stk38), a member of the NDR protein kinase family, is a new type of Hippo signaling protein kinase, which has extensive biological functions in cell life activities. We found that Stk38 molecules can be promoted through previous studies. The ubiquitination of Smurf1 mediated MEKK2, which negatively regulates the inflammatory response mediated by TLR9, participates in the inherent immune response. But it has not been reported in the field of antiviral innate immunity. The present study is about the intrinsic immune response of Hippo signaling molecules represented by Stk38 in the following three parts. The role of the regulatory mechanism in the study. 1, the role of protein kinase Stk38 in the regulation of the expression of IFN- beta in macrophages induced by VSV. This part is mainly through the experiment to explore the regulation of Stk38 molecules against the inherent immune response of the virus. By using small interference RNA technology, the specific target Stk38 in the mouse primary peritoneal macrophages is transferred to the specific target Stk38. After siRNA, the expression level of IFN- beta mRNA was detected by real-time fluorescence quantitative PCR, and the content of IFN- beta in cell supernatant was detected by ELISA. We found that the production ability of IFN- beta induced by VSV infection was significantly decreased. Similarly, it was found in the peritoneal macrophages of the stk38 knockout mice that the production capacity of IFN- beta was seriously damaged after the VSV infection. On the one hand, we obtained the RAW264.7 cell line that stably expressed the exogenous stk38 molecule by drug screening. Compared with the control cell line, the secretory level of the stk38 high expression cell line IFN- beta was raised correspondingly after VSV infection. In addition, we also detected the peritoneal macrophages in Stk38 knockout mice after VSV infection by real-time fluorescent quantitative PCR technique. The nucleic acid components of the VSV virus found that the number of DNA copies of the virus in the stk38 deficient cells increased and the replication ability was stronger compared with the control cells. We also established the VSV acute infection model in the stk38 deficient mice. By detecting the secretion of IFN- beta in the serum of the mice, we found that the acute VSV infection, the defective mice after the acute VSV infection. The secretion of IFN- beta in the serum decreased significantly. At the same time, the survival rate of Stk38 deficient mice was also lower than that in the same nest control wild type mice. Through the experimental results, we confirmed that Stk38 has a positive regulatory effect on the secretion of IFN- beta in macrophages induced by VSV, and can inhibit the proliferation of the virus and also protect the virus infected mice in the body. Protection. Two, Hippo signal effect molecule YAP regulates the expression of IFN- beta in VSV induced macrophages because Stk38 is a regulator of Hippo signaling pathway. Therefore, in order to discover the regulation mechanism of Stk38 on the secretion of IFN- beta, we designed the experiment to explore whether the Hippo pathway's response molecule Yap participates in Stk38 on the expression of IFN- beta. Control. Stk38 deletion in mouse peritoneal macrophages increased the level of YAP expression. But siRNA transfected with Yap molecules had no effect on the ability to express IFN- beta, indicating that YAP had no regulatory effect on IFN- beta. The above results showed that the regulation of Stk38 molecules on IFN- beta was carried out through non dependence of YAP. Three, Stk38 score. The molecular mechanism of the expression of IFN- beta induced by VSV is the main content of the specific molecular mechanism related to the regulation of the expression of IFN- beta by Stk38. Through screening of the activation of interferon related signaling pathway, we found that the phosphorylated water of the interferon related pathway signal molecule STAT1 in the Stk38 deficient cells induced by VSV infection Level reduction suggests that Stk38 may regulate the production of IFN- beta by regulating the activation level of STAT1. Through literature review, we found that glycogen synthase kinase 3 (GSK3) molecules have a positive regulatory effect on the activation of STAT1. Therefore, we use small interference RNA or specific inhibitor CHIR-99021 to treat cells, and find out GSK3 on GSK3. Inhibition of molecules can indeed reduce the activation of VSV induced STAT1 and the expression of IFN- beta. At the same time, the high expression vector transfected with related molecules in HEK293 cells, we found that the Stk38 molecule can bind to the GSK3 molecule and protect the activity of GSK3 by blocking the mechanism of the phosphorylation of GSK3 by the Akt. Finally, CHIR-99021 can be blocked. We have proved that Stk38 can promote the synthesis and secretion of IFN- beta induced by VSV infection by adjusting the GSK3-STAT1 signal to promote the synthesis and secretion of IFN- beta by regulating the GSK3-STAT1 signal. In summary, we have proved that the new protein kinase Stk38 of the Hippo signaling pathway can be passed through the GSK3-STAT1 signal path through the experiment. Diameter, promoting the synthesis and secretion of IFN- beta induced by VSV infection. Our study first found that Stk38 molecules play a regulatory role in the antiviral inherent immune response, and preliminarily discussed its mechanism of action. It is suggested that Stk38 molecules can interact with GSK3 molecules and promote IFN- beta secretion through GSK3-STAT1 signals to enhance the body's antiviral activity. The discovery of the regulation of the secretion of IFN- beta by Stk38 further enriches the biological function of Stk38 to make a new understanding of the function of the molecule; on the other hand, it has also developed a part of the signal network against the regulation of the inherent immune response of the virus, and provides a new way of thinking for the study of the regulation mechanism of IFN- beta secretion. The treatment of viral infectious diseases provides a potential new target.
【学位授予单位】：第二军医大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R392
本文编号：2156396
[Abstract]:Innate immunity, also known as the natural immune (natural immunity), is the body's own defense ability to resist the invasion of foreign pathogens. The intrinsic immune response is initiated by the recognition of the Pattern recognition receptors (PRRs) on the relative conservatives in the pathogen. These pathogens are relatively conservative. Pathogen associated molecular Patterns (PAMPs), which is known as the pathogen associated molecular model (PAMPs), is necessary in the survival or pathogenesis of the pathogen. After the pattern recognition receptor recognizes the corresponding ligand, it can activate the downstream signal molecules through a series of signal transduction pathways, causing inflammatory cytokines and type I interferon and other immunization. The secretion of the medium promotes the body's immune response. Identification and response to the virus components are an important part of the inherent immune response. The identification of viral nucleic acids is mainly through the TLRs, RLRs and viral double stranded DNA recognition molecules that are a class of membrane receptor families, and TLR3, TLR7 and TLR8 exist on the intracellular membrane of the virus. To identify the virus components in the internal body. After the virus is phagocyted, its nucleic acid components will be exposed to the phagocytic inner body. After binding to the corresponding ligand, TLRs can transmit molecules through the joint protein TRIF or MyD88 respectively through the downstream signal transduction molecules, activating IRF3, IRF7 and NF- kappa B, promoting the secretion of.RLRs mainly by type I interferon and inflammatory cytokines. Responsible for identifying the RNA components of the cytoplasm of the cytoplasm, including two receptors of RIG-I and MDA-5. After the virus infected cells, the nucleic acid components entered the cytoplasm, activated by the RLRs recognition.RLRs, and recruited the joint molecule MAVS, further activating the downstream signal pathway, phosphorylated IRF3, IRF7, and NF- kappa B, inducing type I interferon and inflammatory cytokine production. The virus double stranded DNA recognition molecules are numerous, mainly through the joint protein STING activating the downstream signal pathway, phosphorylated IRF3, IRF7 and NF- kappa B, inducing type I interferon and inflammatory cytokine production. Activation and activation of tyrosine protein kinase Jak1 (Janus kinase 1) and Tyk2 (tyrosine kinase 2) activate the transcription of a large number of interferon induced genes (IFN-stimulated genes, ISGs) downstream by Jak-STAT signaling pathway, thereby enhancing the body's anti-virus ability and also reacting on the pattern recognition signaling pathway to further promote I The production of type IFN interferon produces a full amount of interferon I in short time by positive feedback, and the STAT1 molecule plays an important role in the activation of this pathway. In addition to the activation of the upstream interferon signal, STAT1 can also be activated directly by the MAVS non dependent signal after activation of RIG-I. The complexity of the interferon signaling network shows that the regulation of the type I interferon secretion is also a very complex system. The regulatory mechanism of type I interferon is a hot issue in the field of inherent immunity. It is also helpful for us to better understand the mechanism of antiviral inherent immune response and to find out the mechanism of antiviral innate immune response. The potential treatment strategy for finding infectious diseases. Serine / threonine protein kinase 38 (Serine/threoninekinase38, Stk38), a member of the NDR protein kinase family, is a new type of Hippo signaling protein kinase, which has extensive biological functions in cell life activities. We found that Stk38 molecules can be promoted through previous studies. The ubiquitination of Smurf1 mediated MEKK2, which negatively regulates the inflammatory response mediated by TLR9, participates in the inherent immune response. But it has not been reported in the field of antiviral innate immunity. The present study is about the intrinsic immune response of Hippo signaling molecules represented by Stk38 in the following three parts. The role of the regulatory mechanism in the study. 1, the role of protein kinase Stk38 in the regulation of the expression of IFN- beta in macrophages induced by VSV. This part is mainly through the experiment to explore the regulation of Stk38 molecules against the inherent immune response of the virus. By using small interference RNA technology, the specific target Stk38 in the mouse primary peritoneal macrophages is transferred to the specific target Stk38. After siRNA, the expression level of IFN- beta mRNA was detected by real-time fluorescence quantitative PCR, and the content of IFN- beta in cell supernatant was detected by ELISA. We found that the production ability of IFN- beta induced by VSV infection was significantly decreased. Similarly, it was found in the peritoneal macrophages of the stk38 knockout mice that the production capacity of IFN- beta was seriously damaged after the VSV infection. On the one hand, we obtained the RAW264.7 cell line that stably expressed the exogenous stk38 molecule by drug screening. Compared with the control cell line, the secretory level of the stk38 high expression cell line IFN- beta was raised correspondingly after VSV infection. In addition, we also detected the peritoneal macrophages in Stk38 knockout mice after VSV infection by real-time fluorescent quantitative PCR technique. The nucleic acid components of the VSV virus found that the number of DNA copies of the virus in the stk38 deficient cells increased and the replication ability was stronger compared with the control cells. We also established the VSV acute infection model in the stk38 deficient mice. By detecting the secretion of IFN- beta in the serum of the mice, we found that the acute VSV infection, the defective mice after the acute VSV infection. The secretion of IFN- beta in the serum decreased significantly. At the same time, the survival rate of Stk38 deficient mice was also lower than that in the same nest control wild type mice. Through the experimental results, we confirmed that Stk38 has a positive regulatory effect on the secretion of IFN- beta in macrophages induced by VSV, and can inhibit the proliferation of the virus and also protect the virus infected mice in the body. Protection. Two, Hippo signal effect molecule YAP regulates the expression of IFN- beta in VSV induced macrophages because Stk38 is a regulator of Hippo signaling pathway. Therefore, in order to discover the regulation mechanism of Stk38 on the secretion of IFN- beta, we designed the experiment to explore whether the Hippo pathway's response molecule Yap participates in Stk38 on the expression of IFN- beta. Control. Stk38 deletion in mouse peritoneal macrophages increased the level of YAP expression. But siRNA transfected with Yap molecules had no effect on the ability to express IFN- beta, indicating that YAP had no regulatory effect on IFN- beta. The above results showed that the regulation of Stk38 molecules on IFN- beta was carried out through non dependence of YAP. Three, Stk38 score. The molecular mechanism of the expression of IFN- beta induced by VSV is the main content of the specific molecular mechanism related to the regulation of the expression of IFN- beta by Stk38. Through screening of the activation of interferon related signaling pathway, we found that the phosphorylated water of the interferon related pathway signal molecule STAT1 in the Stk38 deficient cells induced by VSV infection Level reduction suggests that Stk38 may regulate the production of IFN- beta by regulating the activation level of STAT1. Through literature review, we found that glycogen synthase kinase 3 (GSK3) molecules have a positive regulatory effect on the activation of STAT1. Therefore, we use small interference RNA or specific inhibitor CHIR-99021 to treat cells, and find out GSK3 on GSK3. Inhibition of molecules can indeed reduce the activation of VSV induced STAT1 and the expression of IFN- beta. At the same time, the high expression vector transfected with related molecules in HEK293 cells, we found that the Stk38 molecule can bind to the GSK3 molecule and protect the activity of GSK3 by blocking the mechanism of the phosphorylation of GSK3 by the Akt. Finally, CHIR-99021 can be blocked. We have proved that Stk38 can promote the synthesis and secretion of IFN- beta induced by VSV infection by adjusting the GSK3-STAT1 signal to promote the synthesis and secretion of IFN- beta by regulating the GSK3-STAT1 signal. In summary, we have proved that the new protein kinase Stk38 of the Hippo signaling pathway can be passed through the GSK3-STAT1 signal path through the experiment. Diameter, promoting the synthesis and secretion of IFN- beta induced by VSV infection. Our study first found that Stk38 molecules play a regulatory role in the antiviral inherent immune response, and preliminarily discussed its mechanism of action. It is suggested that Stk38 molecules can interact with GSK3 molecules and promote IFN- beta secretion through GSK3-STAT1 signals to enhance the body's antiviral activity. The discovery of the regulation of the secretion of IFN- beta by Stk38 further enriches the biological function of Stk38 to make a new understanding of the function of the molecule; on the other hand, it has also developed a part of the signal network against the regulation of the inherent immune response of the virus, and provides a new way of thinking for the study of the regulation mechanism of IFN- beta secretion. The treatment of viral infectious diseases provides a potential new target.
【学位授予单位】：第二军医大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R392
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