The innate immune system is critical for clearing infection, and is tightly regulated to avert excessive tissue damage. Nod1/2-Rip2 signaling, which is essential for initiating the innate immune response to bacterial ...The innate immune system is critical for clearing infection, and is tightly regulated to avert excessive tissue damage. Nod1/2-Rip2 signaling, which is essential for initiating the innate immune response to bacterial infection and ER stress, is subject to many regulatory mechanisms. In this study, we found that LRRK2, encoded by a gene implicated in Crohn＇s disease, leprosy and familial Parkinson＇s disease, modulates the strength of Nod1/2-Rip2 signaling by enhancing Rip2 phosphorylation. LRRK2 deficiency markedly reduces cytokine production in macrophages upon Nod2 activation by muramyl dipeptide （MDP）, Nod1 activation by D-gamma-Glu-meso-diaminopimelic acid （iE-DAP） or ER stress. Our biochemical study shows that the presence of LRRK2 is necessary for optimal phosphorylation of Rip2 upon NOd2 activation. Therefore, this study reveals that LRRK2 is a new positive regulator of Rip2 and promotes inflammatory cytokine induction through the Nod1/2-Rip2 pathway.展开更多
目的研究白藜芦醇(Resveratrol,RES)通过调节NF-κB/RIP2信号通路来治疗和缓解大鼠膀胱癌的保护作用。方法大鼠构建膀胱癌模型后,白藜芦醇(20 mg/kg)和生理盐水连续灌胃14 d。HE染色法观察膀胱组织形态;Western blot法和实时PCR检测NF-...目的研究白藜芦醇(Resveratrol,RES)通过调节NF-κB/RIP2信号通路来治疗和缓解大鼠膀胱癌的保护作用。方法大鼠构建膀胱癌模型后,白藜芦醇(20 mg/kg)和生理盐水连续灌胃14 d。HE染色法观察膀胱组织形态;Western blot法和实时PCR检测NF-κB、RIP2、Caspase 3和Bcl-2蛋白含量和mRNA含量的表达。结果与对照组相比,模型组和实验组大鼠NF-κB、RIP2和Caspase 3 m RNA和蛋白含量显著升高,Bcl-2 m RNA和蛋白含量显著降低,差异具有统计学意义(P<0.05);与模型组相比,实验组大鼠NF-κB、RIP2和Caspase 3 m RNA和蛋白含量显著降低,Bcl-2 m RNA和蛋白含量显著升高,差异具有统计学意义(P<0.05)。结论 b白藜芦醇能够有效缓解和抑制膀胱癌细胞的生长,且NF-κB/R1P2信号通路在此过程中发挥重要作用。展开更多
目的:研究RIP2在弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)中的表达及其预后意义。方法:通过免疫组织化学染色检测RIP2在GCB型和non-GCB型DLBCL中的表达,同时检测BCL-2和C-MYC的表达情况,结合相关临床病理资料分析RIP2在...目的:研究RIP2在弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)中的表达及其预后意义。方法:通过免疫组织化学染色检测RIP2在GCB型和non-GCB型DLBCL中的表达,同时检测BCL-2和C-MYC的表达情况,结合相关临床病理资料分析RIP2在DLBCL发生发展过程中的作用。结果:RIP2表达与IPI评分为中高危组、Am Arbor分期为Ⅲ+Ⅳ期以及结内病变相关,其差异有统计学意义(P<0.05)。单因素生存分析提示,GCB型DLBCL累计生存率高于non-GCB型(P<0.05)。RIP2+组DLBCL累计生存率低于RIP2-组(P<0.05)。RIP2+DLBCL患者接受R-CHOP治疗者累计生存率高于接受CHOP治疗者(P<0.01)。RIP2在DLBCL细胞株中表达量高于正常人外周血单个核细胞(P<0.01),且在不同亚型中有差异性表达(P<0.01)。结论:RIP2的表达可能与DLBCL不良预后以及特殊类型相关。展开更多
受体相互作用蛋白2(receptor-interacting protein 2,RIP2)属于RIP家族成员,在多种组织中均有分布。RIP2可与多种蛋白相互作用,参与多个受体的信号转导,发挥生理功能,被认为是固有免疫、适应性免疫、凋亡信号途径的重要衔接分子。基于...受体相互作用蛋白2(receptor-interacting protein 2,RIP2)属于RIP家族成员,在多种组织中均有分布。RIP2可与多种蛋白相互作用,参与多个受体的信号转导,发挥生理功能,被认为是固有免疫、适应性免疫、凋亡信号途径的重要衔接分子。基于其特殊的分子结构及生物学功能,RIP2在炎症、肿瘤、自身免疫病等多种疾病中发挥着重要作用。本文就RIP2的结构、生物学功能以及其在相关疾病特别是口腔疾病发生发展中所起作用作一综述。展开更多
Receptors interaction protein 2(RIP2)is a specific adaptor molecule in the downstream of NOD2.The role of RIP2 during foot-and-mouth disease virus(FMDV)infection remains unknown.Here,our results showed that RIP2 inhib...Receptors interaction protein 2(RIP2)is a specific adaptor molecule in the downstream of NOD2.The role of RIP2 during foot-and-mouth disease virus(FMDV)infection remains unknown.Here,our results showed that RIP2 inhibited FMDV replication and played an important role in the activation of IFN-βand NF-κB signal pathways during FMDV infection.FMDV infection triggered RIP2 transcription,while it reduced the expression of RIP2 protein.Detailed analysis showed that FMDV 2B,2C,3C^(pro),and L^(pro) proteins were responsible for inducing the reduction of RIP2 protein.3C^(pro) and L^(pro) are viral proteinases that can induce the cleavage or reduction of many host proteins and block host protein synthesis.The carboxyl terminal 105-C114 and 135-C144 regions of 2B were essential for reduction of RIP2.Our results also showed that the N terminal 1-61 region of 2C were essential for the reduction of RIP2.The 2C-induced reduction of RIP2 was dependent on inducing the reduction of poly(A)-binding protein 1(PABPC1).The interaction between RIP2 and 2C was observed in the context of viral infection,and the residues 1-61 were required for the interaction.These data clarify novel mechanisms of reduction of RIP2 mediated by FMDV.展开更多
基金The authors thank Dr. DC Rubinsztein for generously providing the myc-tagged human Lrrk2 （K1906M） expression plasmid, Dr. Wei Gu for pSpCas9-2A-Puro-MCS and EZ-Guide XH vector, and Dr. Shengdian Wang for THP-1 cells. This work was supported by the National Basic Research Program （973 Program） （No. 2013CB531405）, National Natural Science Foundation of China （Grant Nos. 31422019, 31271521, and 31471337） and the Thousand Young Talents program of China.
文摘The innate immune system is critical for clearing infection, and is tightly regulated to avert excessive tissue damage. Nod1/2-Rip2 signaling, which is essential for initiating the innate immune response to bacterial infection and ER stress, is subject to many regulatory mechanisms. In this study, we found that LRRK2, encoded by a gene implicated in Crohn＇s disease, leprosy and familial Parkinson＇s disease, modulates the strength of Nod1/2-Rip2 signaling by enhancing Rip2 phosphorylation. LRRK2 deficiency markedly reduces cytokine production in macrophages upon Nod2 activation by muramyl dipeptide （MDP）, Nod1 activation by D-gamma-Glu-meso-diaminopimelic acid （iE-DAP） or ER stress. Our biochemical study shows that the presence of LRRK2 is necessary for optimal phosphorylation of Rip2 upon NOd2 activation. Therefore, this study reveals that LRRK2 is a new positive regulator of Rip2 and promotes inflammatory cytokine induction through the Nod1/2-Rip2 pathway.
文摘目的研究白藜芦醇(Resveratrol,RES)通过调节NF-κB/RIP2信号通路来治疗和缓解大鼠膀胱癌的保护作用。方法大鼠构建膀胱癌模型后,白藜芦醇(20 mg/kg)和生理盐水连续灌胃14 d。HE染色法观察膀胱组织形态;Western blot法和实时PCR检测NF-κB、RIP2、Caspase 3和Bcl-2蛋白含量和mRNA含量的表达。结果与对照组相比,模型组和实验组大鼠NF-κB、RIP2和Caspase 3 m RNA和蛋白含量显著升高,Bcl-2 m RNA和蛋白含量显著降低,差异具有统计学意义(P<0.05);与模型组相比,实验组大鼠NF-κB、RIP2和Caspase 3 m RNA和蛋白含量显著降低,Bcl-2 m RNA和蛋白含量显著升高,差异具有统计学意义(P<0.05)。结论 b白藜芦醇能够有效缓解和抑制膀胱癌细胞的生长,且NF-κB/R1P2信号通路在此过程中发挥重要作用。
文摘目的:研究RIP2在弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)中的表达及其预后意义。方法:通过免疫组织化学染色检测RIP2在GCB型和non-GCB型DLBCL中的表达,同时检测BCL-2和C-MYC的表达情况,结合相关临床病理资料分析RIP2在DLBCL发生发展过程中的作用。结果:RIP2表达与IPI评分为中高危组、Am Arbor分期为Ⅲ+Ⅳ期以及结内病变相关,其差异有统计学意义(P<0.05)。单因素生存分析提示,GCB型DLBCL累计生存率高于non-GCB型(P<0.05)。RIP2+组DLBCL累计生存率低于RIP2-组(P<0.05)。RIP2+DLBCL患者接受R-CHOP治疗者累计生存率高于接受CHOP治疗者(P<0.01)。RIP2在DLBCL细胞株中表达量高于正常人外周血单个核细胞(P<0.01),且在不同亚型中有差异性表达(P<0.01)。结论:RIP2的表达可能与DLBCL不良预后以及特殊类型相关。
文摘受体相互作用蛋白2(receptor-interacting protein 2,RIP2)属于RIP家族成员,在多种组织中均有分布。RIP2可与多种蛋白相互作用,参与多个受体的信号转导,发挥生理功能,被认为是固有免疫、适应性免疫、凋亡信号途径的重要衔接分子。基于其特殊的分子结构及生物学功能,RIP2在炎症、肿瘤、自身免疫病等多种疾病中发挥着重要作用。本文就RIP2的结构、生物学功能以及其在相关疾病特别是口腔疾病发生发展中所起作用作一综述。
基金This work was supported by Grants from the National Key R&D Programme of China(No.2017YFD0501103 and 2017YFD0501800)the Key Development and Research Foundation of Yunnan(No.2018BB004)the Chinese Academy of Agricultural Science and Technology Innovation Project(CAAS-XTCX2016011-01 and Y2017JC55).
文摘Receptors interaction protein 2(RIP2)is a specific adaptor molecule in the downstream of NOD2.The role of RIP2 during foot-and-mouth disease virus(FMDV)infection remains unknown.Here,our results showed that RIP2 inhibited FMDV replication and played an important role in the activation of IFN-βand NF-κB signal pathways during FMDV infection.FMDV infection triggered RIP2 transcription,while it reduced the expression of RIP2 protein.Detailed analysis showed that FMDV 2B,2C,3C^(pro),and L^(pro) proteins were responsible for inducing the reduction of RIP2 protein.3C^(pro) and L^(pro) are viral proteinases that can induce the cleavage or reduction of many host proteins and block host protein synthesis.The carboxyl terminal 105-C114 and 135-C144 regions of 2B were essential for reduction of RIP2.Our results also showed that the N terminal 1-61 region of 2C were essential for the reduction of RIP2.The 2C-induced reduction of RIP2 was dependent on inducing the reduction of poly(A)-binding protein 1(PABPC1).The interaction between RIP2 and 2C was observed in the context of viral infection,and the residues 1-61 were required for the interaction.These data clarify novel mechanisms of reduction of RIP2 mediated by FMDV.
