BCL10激活转录及其介导细菌脂多糖和TCR信号通路的机制研究
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摘要
一、BCL10同Pellino2的相互作用参与介导TLR4通路
先天免疫又称固有免疫或天然免疫,是机体防御病原体的第一道防线。在先天免疫系统中,不同吞噬细胞如嗜中性粒细胞和树突细胞等通过来自Toll样受体(TLR)的信号而辨别出病原体及“自己”。在启动先天免疫对抗病原体的过程中最重要的一步就是识别,由杀伤细胞的受体识别存在于病原体而不存在于细胞中的成分,称为病原体相关分子模式(pathogen-associated molecular pattern,PAMP)。不同的TLR识别的PAMP不同,例如TLR4可以识别革兰氏阴性菌的LPS。在这里,我们证明T细胞和IκB激酶复合体间的重要信号分子BCL10与先天免疫系统有关,并参与了TLR4途径及核因子κB(NF-κB)的激活。在受到微生物脂多糖(Lipopolysaccharide,LPS)的刺激后,BCL10被招募到TLR4信号复合物上并与Pellino2结合。
Pellino蛋白在TLR信号亚通路的建立和维持中发挥着重要的作用。Pellino2是一个新的信号传导分子。近期研究表明外源鼠pellino2反意(antisense)重组表达能抑制LPS诱导的NF-κB的活化。为找到BCL10相关的信号转导途径的成员,我们用T7 Select噬菌体展示技术分别从肺及肝癌cDNA文库中筛选到6个阳性克隆,其序列编码人的Pellino2 cDNA的部分片段。在LPS刺激的巨噬细胞中,BCL10同Pellino2的体内相互作用通过免疫共沉淀技术得到证明,同时,我们发现Pellino2蛋白的169～233氨基酸区参与介导与BCL10相互作用。为进一步研究Pellino2在BCL10依赖的信号转导途径中的作用,我们通过siRNA重组质粒pSUPER-Pellino2构建了Pellino2表达沉默的细胞系。在该细胞系中,我们发现LPS诱导或BCL10过表达所引
1. BCLIO takes part in TLR4 signaling through the interaction with Pellino2The innate immune response in vertebrates is the first line of defense against invading microorganisms. In innate immunity, different phagocytes such as neutrophils, macrophages and dendritic cells play crucial roles in discrimination between pathogens and self by utilizing signals from the Toll-like receptors(TLR). The most significant step in the process of initiating innate immunity to resist pathogens is recognition, the components, exist in pathogens instead of in cells, which is called pathogen-associated molecular pattern(PAMP), can be recognized by the receptors of killing cells. Different PAMPs are identified by different TLRs, for example, TLR4 can respond to LPS of Gram-negative bacteria. Herein, we demonstrated that BCL10, a critical molecule signaling between the TCR and IκB kinase complexes, was implicated in the innate immunity system and required for appropriate TLR4 pathway and NF-κB activation. In response to LPS stimulation, BCLIO was recruited to TLR4 signaling complexes and associated with Pellino2.Pellino proteins play important roles in establishing and maintaining TLR signal subways. Pellino2 is a newly identified signaling molecule in this process. Recent studies reveal that ectopic expression of a mouse Pellino2 antisense construct can inhibit LP S induced activation of NF-kB. To identify components in BCLIO related signaling pathways we performed a screen for BCL10-associated proteins using T7 select phage display systerm and six positive clones, encoding sequences identical to human Pellino2, were identified
from lung cDNA library and liver tumor cDNA library. In macrophages stimulated by LPS, the interaction in vivo between BCL10 and Pellino2 was demonstrated by co-immunoprecipitation. At the same time, we found the interaction is mediated by the amino acids 169-233 of Pellino2. To further investigate the role of Pellino2 in BCL10 dependent signaling, we designed a SiRNA construct pSUPER-Pellino2 to found a Pellino2 deficient cell line, in which the NF-kB activation was partly inhibited in response to LPS stimulation or BCL10 over-expression, suggests that Pellino2 have an important role in LPS pathway or BCLlO-dependent signaling, it also reveals that BCL10 transmit signals from TLR to Pellino2.To verify the signal transduction of BCL10 in LPS/TLR4 pathway, we use the dominant negative forms of Pellino2 and TAKl to inhibit NF-kB activation in response to over-expresses BCL10. The results pointed that the dominant negative forms of the two LPS/TLR4 specific adaptive molecules performed as we expected. Since both Pellino2 and TAKl are functionally important signaling molecules in Toll-like pathway, these results demonstrate that BCL10 function as a signal molecule in the classical innate immunity. Furthermore, it should be noted that Pellino2 truncated mutant and DN-TAK1 could not completely abolish BCL10 induced NF-kB activation, which indicates that BCL10 also play an essential role in other pathways. Otherwise, IKKP is a common adaptive molecule which is shared by many different signaling pathways, compared to the block effect of DN-Pellino2 and DN-TAK1, DN-IKK|3 has a more intense inhibition to NF-kB activation in response to over-expression of BCL10, which has suggest that BCL10 may join in other pathways other than TLR4 pathway, such as TCR signaling pathway.At the other hand, we transfected cells with SiRNA construct pSUPER-BCLlO to form bcllO gene silent cell line, we found that deficiency in BCL10 expression caused moderate reduction of NF-kB activation in response to LPS stimulation, whereas NF-kB activation triggered by TNF-a treatment was similar in both wild type and BCLlO-deficient cells, which directly give rise to a possibility that BCL10 might specifically signal downstream of TLR4. In subsequent research, after LPS stimulation, endogenous TLR4 co-precipitated with BCL10, indicating that BCL10 may be recruited to the TLR4 signal and be recruited to TLR4 signal complex. However, the RAW264.7 cells defect in Pellino2
expression had no effect on the recruitment of BCLIO, which confirms that Pellino2 is an adaptor downstream of BCLIO in LPS signaling.Although Pellino2 can activate AP-1 and Elk-1, we found that activation of AP-1 and Elk-1 signaling pathways post LPS stimulation was equivalent in both wild type and BCLIO deficient cells, indicating that the defect in BCLIO expression was specific for NF-kB signaling downstream of the Toll-like receptor, but not for other parallel pathways initiated by LPS stimulation.2. SOCS3 blocks TLR4 and TCR signaling through its targeting and interacting with BCLIO2.1 In the screen for BCLIO associated proteins using T7 select phage display system(lung cDNA library and liver tumor cDNA library), we found eight positive clones, which encode sequences partly identical to human SOCS3. It has been reported that SOCS3 is a negative regulator in LPS/TLR4 pathway and TCR pathway. To confirm the exact role SOCS3 plays in LPS pathway and whether BCLIO is the target of SOCS3, we carried out co-immunoprecipitation to study the binding activity of BCLIO and SOCS3 in vivo, consistent with the results showed in phage display screening, we demonstrated that over-expressed SOCS3 could associated with BCLIO in cells stimulated with LPS or untreat. To get further proof, a cell line stably expressing SOCS3 was constructed and forced expression of SOCS3 was found to result in attenuation of BCLlO-induce NF-kB activation and iNOS expression, indicating that BCLIO may be the targeted molecule of SOCS3 for negative regulation in LPS signaling. While in the same cell line, when SOCS3 is forced expressed, the association between BCLIO and Pellino2 was severely impaired, whereas BCLIO interact with more SOCS3 proteins compared to that in the wild type cells. However, neither Pellino2 was detected in SOCS3-precipitated complex, nor was SOCS3 in the Pellino2-precipitated complex, demonstrating that there is no association betweern SOCS3 and Pellino2. Together, SOCS3 may negatively regulate BCLIO function by declining its ability to interact with Pellino2.Synchronously, forced expression of SOCS3 completely abolished the recruitment of BCLIO to TLR4 signaling complex. Taken together, SOCS3 negatively regulate LPS
signaling by facilitating seclusion of BCLIO to receptor complex and subsequently block the signal transmitted through BCLIO. It is very interesting that SOCS3 could also block the association between BCLIO and its downstream adaptor Pellino2, which suggest that BCLIO binding to SOCS3 may result in a complete loss of function in LPS signaling pathway.To examine if the recruitment of endogenous BCLIO to TLR4 signaling complex is time-dependent and negatively.regulated by endogenous SOCS3, we stimulated RAW264.7 cells with LPS and used anti-BCLlO antibody to precipitate BCLIO signaling complex. Endogenous TLR4 in the precipitated signaling complex was immunoblotted by anti-TLR4 antibody and its amount peaked at 30 min after stimulation whereas decreased thereafter and declined to lowest after 60 min. Notably, time kinetics revealed that association between SOCS3 and BCLIO emerged at 30min, peaked at 120 min and declined thereafter. Because LPS-induced expression of SOCS3 was increasing before 120 min after LPS stimulation, association between SOCS3 and BCLIO was evidently independent on LPS stimulation, whereas exhibited a SOCS3 expression-dependent manner.2.2 We carried out phage display screen and identified a key sequence QRHFF as a crucial binding motif for BCLIO and SOCS3, the same motif is found in the SH2 domain of SOCS3. In these years, it has been well documented that divergent SH2 domain play an important role in protein binding specificity. A series of mutant SOCS3 were generated by substitution with each residue of QRHFF motif(Q/D,R/K,H/N,Fl/L,F2/L), the result from immunoprecipitation assay demonstrated that any substitution in SOCS3 completely abrogated interaction between SOCS3 and BCLIO. These results indicated that association between SOCS3 and BCLIO was dependent on the QRHFF in the SH2 domain and, moreover, individual residue in this 5mer motif may differentially contribute to the interaction.Due to the sequence conservation of SOCS1 and SOCS3, we assumed whether the QRHFF substitutes QRWCFF in SH2 domain of SOCS1 makes it possible of SOCS1 binding to BCLIO? Compellingly, a certain extent of association was observed in co-immunoprecipitation, demonstrating that QRHFF motif is essential for BCLIO binding.
These results have defined the specific amino acids in the SH2 domain controlled the specificity for interactions with protein partners and have indicated QRHFF is the minimal functional domain for the binding of SOCS3 and BCLIO.To further verify the inhibitory function of SOCS3 in the TCR sigaling is correlated to BCLIO, we speculate if SOCS3 would interfere with the functional synergy between BCLIO and MALTl. In the Jurkat cells stably expressing wt-SOCS3 with stimulation of PMA, the interaction between BCLIO and MALTl was completely abolished, whereas not in the Jurkat cells stably expressing mtSOCS3(QRHFF-*QRNFF). Moreover, the NF-kB activation level in these cells was examined following stimulation of PMA. While stable expression of ectopic wt-SOCS3 severely attenuated mutant form of SOCS3 was similar with that in the wild type Jurkat T cells. To study whether the transient suppression of SOCS3 expression would be functionally relevant to formation of ternary protein complex, an RNAi construct pSUPER-SOCS3 was transiently transfected in the Jurkat cells. We observed that a transient decline in SOCS3 expression markedly enhanced both the BCL10-MALT1 association and NF-kB activation induced by PMA stimulation. These results have revealed that the interaction between SOCS3 and BCLIO has inhibited the interaction of BCLIO and MALTl, thus attenuated the activation of NF-kB.3. BCLIO is a potential transcriptional activatorIn our previous work, we have found BCLIO is a transcriptional activator in yeast, it's a completely new function of BCLIO, on which our research are based. GAL4 fusion protein is a widely used transcriptional factor in determining the activity of transactivation. In our research, we use luciferase reporter plasmid to report the transcriptional function of BCLIO in mammalian cells, and we found, the wild type BCLIO exhibited maximum transactivation, the construct lacking N-terminal 13 amino acids (amino acids 14-90, 14-233 and 91-233) failed to transactivate, whereas the constructs containing this region (amino acids 1-13 and 1-90) exhibited considerable transactivation activity. The results suggest that the region containing N-terminal 13 amino acids is necessary for transactivation.When we carried our immunodepletion, we observed that BCLIO has a direct
interaction with general transcription factor TFII B, the result is also confirmed by the following pull-down assay and co-immunoprecipitation. The interaction between BCL10 and TFIIB is mediated by the N-terminal 13 amino acids. On the other side, we found the BCLlO-dependent transactivation effect would be enhanced by the over-expression of TFIIB, this effect also depends on the N-terminal 13 amino acids, and was lost when it was deleted. Taken together, our data support that BCL10-dependent transactivation is mediated through direct interaction with TF IIB.
先天免疫又称固有免疫或天然免疫,是机体防御病原体的第一道防线。在先天免疫系统中,不同吞噬细胞如嗜中性粒细胞和树突细胞等通过来自Toll样受体(TLR)的信号而辨别出病原体及“自己”。在启动先天免疫对抗病原体的过程中最重要的一步就是识别,由杀伤细胞的受体识别存在于病原体而不存在于细胞中的成分,称为病原体相关分子模式(pathogen-associated molecular pattern,PAMP)。不同的TLR识别的PAMP不同,例如TLR4可以识别革兰氏阴性菌的LPS。在这里,我们证明T细胞和IκB激酶复合体间的重要信号分子BCL10与先天免疫系统有关,并参与了TLR4途径及核因子κB(NF-κB)的激活。在受到微生物脂多糖(Lipopolysaccharide,LPS)的刺激后,BCL10被招募到TLR4信号复合物上并与Pellino2结合。
Pellino蛋白在TLR信号亚通路的建立和维持中发挥着重要的作用。Pellino2是一个新的信号传导分子。近期研究表明外源鼠pellino2反意(antisense)重组表达能抑制LPS诱导的NF-κB的活化。为找到BCL10相关的信号转导途径的成员,我们用T7 Select噬菌体展示技术分别从肺及肝癌cDNA文库中筛选到6个阳性克隆,其序列编码人的Pellino2 cDNA的部分片段。在LPS刺激的巨噬细胞中,BCL10同Pellino2的体内相互作用通过免疫共沉淀技术得到证明,同时,我们发现Pellino2蛋白的169～233氨基酸区参与介导与BCL10相互作用。为进一步研究Pellino2在BCL10依赖的信号转导途径中的作用,我们通过siRNA重组质粒pSUPER-Pellino2构建了Pellino2表达沉默的细胞系。在该细胞系中,我们发现LPS诱导或BCL10过表达所引
1. BCLIO takes part in TLR4 signaling through the interaction with Pellino2The innate immune response in vertebrates is the first line of defense against invading microorganisms. In innate immunity, different phagocytes such as neutrophils, macrophages and dendritic cells play crucial roles in discrimination between pathogens and self by utilizing signals from the Toll-like receptors(TLR). The most significant step in the process of initiating innate immunity to resist pathogens is recognition, the components, exist in pathogens instead of in cells, which is called pathogen-associated molecular pattern(PAMP), can be recognized by the receptors of killing cells. Different PAMPs are identified by different TLRs, for example, TLR4 can respond to LPS of Gram-negative bacteria. Herein, we demonstrated that BCL10, a critical molecule signaling between the TCR and IκB kinase complexes, was implicated in the innate immunity system and required for appropriate TLR4 pathway and NF-κB activation. In response to LPS stimulation, BCLIO was recruited to TLR4 signaling complexes and associated with Pellino2.Pellino proteins play important roles in establishing and maintaining TLR signal subways. Pellino2 is a newly identified signaling molecule in this process. Recent studies reveal that ectopic expression of a mouse Pellino2 antisense construct can inhibit LP S induced activation of NF-kB. To identify components in BCLIO related signaling pathways we performed a screen for BCL10-associated proteins using T7 select phage display systerm and six positive clones, encoding sequences identical to human Pellino2, were identified
from lung cDNA library and liver tumor cDNA library. In macrophages stimulated by LPS, the interaction in vivo between BCL10 and Pellino2 was demonstrated by co-immunoprecipitation. At the same time, we found the interaction is mediated by the amino acids 169-233 of Pellino2. To further investigate the role of Pellino2 in BCL10 dependent signaling, we designed a SiRNA construct pSUPER-Pellino2 to found a Pellino2 deficient cell line, in which the NF-kB activation was partly inhibited in response to LPS stimulation or BCL10 over-expression, suggests that Pellino2 have an important role in LPS pathway or BCLlO-dependent signaling, it also reveals that BCL10 transmit signals from TLR to Pellino2.To verify the signal transduction of BCL10 in LPS/TLR4 pathway, we use the dominant negative forms of Pellino2 and TAKl to inhibit NF-kB activation in response to over-expresses BCL10. The results pointed that the dominant negative forms of the two LPS/TLR4 specific adaptive molecules performed as we expected. Since both Pellino2 and TAKl are functionally important signaling molecules in Toll-like pathway, these results demonstrate that BCL10 function as a signal molecule in the classical innate immunity. Furthermore, it should be noted that Pellino2 truncated mutant and DN-TAK1 could not completely abolish BCL10 induced NF-kB activation, which indicates that BCL10 also play an essential role in other pathways. Otherwise, IKKP is a common adaptive molecule which is shared by many different signaling pathways, compared to the block effect of DN-Pellino2 and DN-TAK1, DN-IKK|3 has a more intense inhibition to NF-kB activation in response to over-expression of BCL10, which has suggest that BCL10 may join in other pathways other than TLR4 pathway, such as TCR signaling pathway.At the other hand, we transfected cells with SiRNA construct pSUPER-BCLlO to form bcllO gene silent cell line, we found that deficiency in BCL10 expression caused moderate reduction of NF-kB activation in response to LPS stimulation, whereas NF-kB activation triggered by TNF-a treatment was similar in both wild type and BCLlO-deficient cells, which directly give rise to a possibility that BCL10 might specifically signal downstream of TLR4. In subsequent research, after LPS stimulation, endogenous TLR4 co-precipitated with BCL10, indicating that BCL10 may be recruited to the TLR4 signal and be recruited to TLR4 signal complex. However, the RAW264.7 cells defect in Pellino2
expression had no effect on the recruitment of BCLIO, which confirms that Pellino2 is an adaptor downstream of BCLIO in LPS signaling.Although Pellino2 can activate AP-1 and Elk-1, we found that activation of AP-1 and Elk-1 signaling pathways post LPS stimulation was equivalent in both wild type and BCLIO deficient cells, indicating that the defect in BCLIO expression was specific for NF-kB signaling downstream of the Toll-like receptor, but not for other parallel pathways initiated by LPS stimulation.2. SOCS3 blocks TLR4 and TCR signaling through its targeting and interacting with BCLIO2.1 In the screen for BCLIO associated proteins using T7 select phage display system(lung cDNA library and liver tumor cDNA library), we found eight positive clones, which encode sequences partly identical to human SOCS3. It has been reported that SOCS3 is a negative regulator in LPS/TLR4 pathway and TCR pathway. To confirm the exact role SOCS3 plays in LPS pathway and whether BCLIO is the target of SOCS3, we carried out co-immunoprecipitation to study the binding activity of BCLIO and SOCS3 in vivo, consistent with the results showed in phage display screening, we demonstrated that over-expressed SOCS3 could associated with BCLIO in cells stimulated with LPS or untreat. To get further proof, a cell line stably expressing SOCS3 was constructed and forced expression of SOCS3 was found to result in attenuation of BCLlO-induce NF-kB activation and iNOS expression, indicating that BCLIO may be the targeted molecule of SOCS3 for negative regulation in LPS signaling. While in the same cell line, when SOCS3 is forced expressed, the association between BCLIO and Pellino2 was severely impaired, whereas BCLIO interact with more SOCS3 proteins compared to that in the wild type cells. However, neither Pellino2 was detected in SOCS3-precipitated complex, nor was SOCS3 in the Pellino2-precipitated complex, demonstrating that there is no association betweern SOCS3 and Pellino2. Together, SOCS3 may negatively regulate BCLIO function by declining its ability to interact with Pellino2.Synchronously, forced expression of SOCS3 completely abolished the recruitment of BCLIO to TLR4 signaling complex. Taken together, SOCS3 negatively regulate LPS
signaling by facilitating seclusion of BCLIO to receptor complex and subsequently block the signal transmitted through BCLIO. It is very interesting that SOCS3 could also block the association between BCLIO and its downstream adaptor Pellino2, which suggest that BCLIO binding to SOCS3 may result in a complete loss of function in LPS signaling pathway.To examine if the recruitment of endogenous BCLIO to TLR4 signaling complex is time-dependent and negatively.regulated by endogenous SOCS3, we stimulated RAW264.7 cells with LPS and used anti-BCLlO antibody to precipitate BCLIO signaling complex. Endogenous TLR4 in the precipitated signaling complex was immunoblotted by anti-TLR4 antibody and its amount peaked at 30 min after stimulation whereas decreased thereafter and declined to lowest after 60 min. Notably, time kinetics revealed that association between SOCS3 and BCLIO emerged at 30min, peaked at 120 min and declined thereafter. Because LPS-induced expression of SOCS3 was increasing before 120 min after LPS stimulation, association between SOCS3 and BCLIO was evidently independent on LPS stimulation, whereas exhibited a SOCS3 expression-dependent manner.2.2 We carried out phage display screen and identified a key sequence QRHFF as a crucial binding motif for BCLIO and SOCS3, the same motif is found in the SH2 domain of SOCS3. In these years, it has been well documented that divergent SH2 domain play an important role in protein binding specificity. A series of mutant SOCS3 were generated by substitution with each residue of QRHFF motif(Q/D,R/K,H/N,Fl/L,F2/L), the result from immunoprecipitation assay demonstrated that any substitution in SOCS3 completely abrogated interaction between SOCS3 and BCLIO. These results indicated that association between SOCS3 and BCLIO was dependent on the QRHFF in the SH2 domain and, moreover, individual residue in this 5mer motif may differentially contribute to the interaction.Due to the sequence conservation of SOCS1 and SOCS3, we assumed whether the QRHFF substitutes QRWCFF in SH2 domain of SOCS1 makes it possible of SOCS1 binding to BCLIO? Compellingly, a certain extent of association was observed in co-immunoprecipitation, demonstrating that QRHFF motif is essential for BCLIO binding.
These results have defined the specific amino acids in the SH2 domain controlled the specificity for interactions with protein partners and have indicated QRHFF is the minimal functional domain for the binding of SOCS3 and BCLIO.To further verify the inhibitory function of SOCS3 in the TCR sigaling is correlated to BCLIO, we speculate if SOCS3 would interfere with the functional synergy between BCLIO and MALTl. In the Jurkat cells stably expressing wt-SOCS3 with stimulation of PMA, the interaction between BCLIO and MALTl was completely abolished, whereas not in the Jurkat cells stably expressing mtSOCS3(QRHFF-*QRNFF). Moreover, the NF-kB activation level in these cells was examined following stimulation of PMA. While stable expression of ectopic wt-SOCS3 severely attenuated mutant form of SOCS3 was similar with that in the wild type Jurkat T cells. To study whether the transient suppression of SOCS3 expression would be functionally relevant to formation of ternary protein complex, an RNAi construct pSUPER-SOCS3 was transiently transfected in the Jurkat cells. We observed that a transient decline in SOCS3 expression markedly enhanced both the BCL10-MALT1 association and NF-kB activation induced by PMA stimulation. These results have revealed that the interaction between SOCS3 and BCLIO has inhibited the interaction of BCLIO and MALTl, thus attenuated the activation of NF-kB.3. BCLIO is a potential transcriptional activatorIn our previous work, we have found BCLIO is a transcriptional activator in yeast, it's a completely new function of BCLIO, on which our research are based. GAL4 fusion protein is a widely used transcriptional factor in determining the activity of transactivation. In our research, we use luciferase reporter plasmid to report the transcriptional function of BCLIO in mammalian cells, and we found, the wild type BCLIO exhibited maximum transactivation, the construct lacking N-terminal 13 amino acids (amino acids 14-90, 14-233 and 91-233) failed to transactivate, whereas the constructs containing this region (amino acids 1-13 and 1-90) exhibited considerable transactivation activity. The results suggest that the region containing N-terminal 13 amino acids is necessary for transactivation.When we carried our immunodepletion, we observed that BCLIO has a direct
interaction with general transcription factor TFII B, the result is also confirmed by the following pull-down assay and co-immunoprecipitation. The interaction between BCL10 and TFIIB is mediated by the N-terminal 13 amino acids. On the other side, we found the BCLlO-dependent transactivation effect would be enhanced by the over-expression of TFIIB, this effect also depends on the N-terminal 13 amino acids, and was lost when it was deleted. Taken together, our data support that BCL10-dependent transactivation is mediated through direct interaction with TF IIB.
引文
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