Objective:The tumor necrosis factor receptor-associated factor 7(TRAF7)is one of the components of the tumor necrosis factor alpha(TNF-α)/nuclear factor kappa B(NF-κB)pathway and a putative E3-ubiquitin ligase.This ...Objective:The tumor necrosis factor receptor-associated factor 7(TRAF7)is one of the components of the tumor necrosis factor alpha(TNF-α)/nuclear factor kappa B(NF-κB)pathway and a putative E3-ubiquitin ligase.This study aims to explore the biologic effects and the molecular mechanisms of deregulated TRAF7 signaling in hepatocellular carcinoma(HCC)progression.展开更多
TRAF7 serves as a crucial intracellular adaptor and E3 ubiquitin ligase involved in signal transduction pathways,contributing to immune responses,tumor progression,and embryonic development.Somatic mutations within th...TRAF7 serves as a crucial intracellular adaptor and E3 ubiquitin ligase involved in signal transduction pathways,contributing to immune responses,tumor progression,and embryonic development.Somatic mutations within the coiled-coil(CC)domain and WD40 repeat domain of TRAF7 could cause brain tumors,while germline pathogenic mutations contribute to severe developmental abnormalities.However,the precise molecular mechanism underlying TRAF7 involvement in embryonic development remains unclear.In this study,we employed zebrafish as an in vivo model system.TRAF7 knock down caused defects in zebrafish embryonic development.We determined the crystal structure of TRAF7 CC domain at 3.3Åresolution and found that the CC region trimerization was essential for TRAF7 functionality during zebrafish embryonic development.Additionally,disease-causing mutations in TRAF7 CC region could impair the trimer formation,consequently impacting early embryonic development of zebrafish.Therefore,our study sheds light on the molecular mechanism of TRAF7 CC trimer formation and its pivotal role in embryonic development.展开更多
TANK-binding kinase 1(TBK1)is a nodal protein involved in multiple signal transduction pathways.In RNA virus-mediated innate immunity,TBK1 is recruited to the prion-like platform formed by MAVS and subsequently activa...TANK-binding kinase 1(TBK1)is a nodal protein involved in multiple signal transduction pathways.In RNA virus-mediated innate immunity,TBK1 is recruited to the prion-like platform formed by MAVS and subsequently activates the transcription factors IRF3/7 and NF-κB to produce type I interferon(IFN)and proinflammatory cytokines for the signaling cascade.In this study,TRAF7 was identified as a negative regulator of innate immune signaling.TRAF7 interacts with TBK1 and promotes K48-linked polyubiquitination and degradation of TBK1 through its RING domain,impairing the activation of IRF3 and the production of IFN-β.In addition,we found that the conserved cysteine residues at position 131 of TRAF7 are necessary for its function toward TBK1.Knockout of TRAF7 could facilitate the activation of IRF3 and increase the transcript levels of downstream antiviral genes.These data suggest that TRAF7 negatively regulates innate antiviral immunity by promoting the K48-linked ubiquitination of TBK1.展开更多
一组7名患有不明原因类似疾病的患者现在知道他们的疾病可能源于遗传。研究人员对患者基因组中的所有蛋白质编码基因进行了测序,并鉴定了TRAF7基因中的四种不同突变。研究人员在American Journal of Human Genetics上报道,这7名患者携...一组7名患有不明原因类似疾病的患者现在知道他们的疾病可能源于遗传。研究人员对患者基因组中的所有蛋白质编码基因进行了测序,并鉴定了TRAF7基因中的四种不同突变。研究人员在American Journal of Human Genetics上报道,这7名患者携带的这些突变都是de novo,不存在于他们的父母身上。实验室研究表明。展开更多
文摘Objective:The tumor necrosis factor receptor-associated factor 7(TRAF7)is one of the components of the tumor necrosis factor alpha(TNF-α)/nuclear factor kappa B(NF-κB)pathway and a putative E3-ubiquitin ligase.This study aims to explore the biologic effects and the molecular mechanisms of deregulated TRAF7 signaling in hepatocellular carcinoma(HCC)progression.
基金funded by Shanghai Jiao Tong University‘Star of Jiao Tong University’Medical-Engineering Cross Research Fund(YG2019QNB01)Shanghai Municipal Key Clinical Specialty(shslczdzk06902)Shanghai Children's Hospital Fund(2022YGZM01).
文摘TRAF7 serves as a crucial intracellular adaptor and E3 ubiquitin ligase involved in signal transduction pathways,contributing to immune responses,tumor progression,and embryonic development.Somatic mutations within the coiled-coil(CC)domain and WD40 repeat domain of TRAF7 could cause brain tumors,while germline pathogenic mutations contribute to severe developmental abnormalities.However,the precise molecular mechanism underlying TRAF7 involvement in embryonic development remains unclear.In this study,we employed zebrafish as an in vivo model system.TRAF7 knock down caused defects in zebrafish embryonic development.We determined the crystal structure of TRAF7 CC domain at 3.3Åresolution and found that the CC region trimerization was essential for TRAF7 functionality during zebrafish embryonic development.Additionally,disease-causing mutations in TRAF7 CC region could impair the trimer formation,consequently impacting early embryonic development of zebrafish.Therefore,our study sheds light on the molecular mechanism of TRAF7 CC trimer formation and its pivotal role in embryonic development.
基金National Natural Science Foundation of China(Grant Nos.81971502,82060298,31570876).
文摘TANK-binding kinase 1(TBK1)is a nodal protein involved in multiple signal transduction pathways.In RNA virus-mediated innate immunity,TBK1 is recruited to the prion-like platform formed by MAVS and subsequently activates the transcription factors IRF3/7 and NF-κB to produce type I interferon(IFN)and proinflammatory cytokines for the signaling cascade.In this study,TRAF7 was identified as a negative regulator of innate immune signaling.TRAF7 interacts with TBK1 and promotes K48-linked polyubiquitination and degradation of TBK1 through its RING domain,impairing the activation of IRF3 and the production of IFN-β.In addition,we found that the conserved cysteine residues at position 131 of TRAF7 are necessary for its function toward TBK1.Knockout of TRAF7 could facilitate the activation of IRF3 and increase the transcript levels of downstream antiviral genes.These data suggest that TRAF7 negatively regulates innate antiviral immunity by promoting the K48-linked ubiquitination of TBK1.
文摘一组7名患有不明原因类似疾病的患者现在知道他们的疾病可能源于遗传。研究人员对患者基因组中的所有蛋白质编码基因进行了测序,并鉴定了TRAF7基因中的四种不同突变。研究人员在American Journal of Human Genetics上报道,这7名患者携带的这些突变都是de novo,不存在于他们的父母身上。实验室研究表明。
