The mitogen-activated protein kinase (MAPK) p38α is a key regulator in many cellular processes, whose activity is tightly regulated by upstream kinases, phosphatases and other regulators. Transforming growth factor-...The mitogen-activated protein kinase (MAPK) p38α is a key regulator in many cellular processes, whose activity is tightly regulated by upstream kinases, phosphatases and other regulators. Transforming growth factor-β activated kinase 1 (TAK1) is an upstream kinase in p38α signaling, and its full activation requires a specific activator, the TAK1-binding protein (TAB1). TAB1 was also shown to be an inducer of p38α's autophosphorylation and/or a substrate driving the feedback control of p38α signaling. Here we determined the complex structure of the unphosphorylated p38α and a docking peptide of TAB1, which shows that the TAB1 peptide binds to the classical MAPK docking groove and induces long-range conformational changes on p38α. Our structural and biochemical analyses suggest that TAB1 is a reasonable substrate of p38α, yet the interaction between the docking peptide and p38α may not be sufficient to trigger trans-autophosphorylation of p38α.展开更多
Although microRNA-155(miR-155)is considered a pro-inflammatory mediator,cumulative evidence indicates that it also has anti-inflammatory effects in macrophages and dendritic cells.In this study,we identified the drama...Although microRNA-155(miR-155)is considered a pro-inflammatory mediator,cumulative evidence indicates that it also has anti-inflammatory effects in macrophages and dendritic cells.In this study,we identified the dramatic expression changes of more than half of potential miR-155-targeted genes upon lipopolysaccharide(LPS)stimulation;223 genes were down-regulated and 85 genes were up-regulated,including suppressor of cytokine signaling 1(SOCS1)and transforming growth factor-β-activated kinase 1-binding protein 2(TAB2),two well-known genes involved in miR-155-mediated regulation of the Toll-like receptor 4(TLR4)signaling pathway.We also found that miR-155 acted as an anti-inflammatory mediator in the initial stage of LPS-induced inflammatory response mainly through repressing TAB2 protein translation,and as a proinflammatory mediator by down-regulating SOCS1 in the later stage.Meanwhile,overexpression of TAB23'untranslated region(UTR)in macrophages promoted the development of endotoxin tolerance by competing for binding with miR-155,which resulted in an elevated expression level of SOCS1 protein.These findings provide new insights for understanding the regulatory mechanisms in fine-tuning of LPS-induced innate immune response.展开更多
基金supported in part by National Natural Science Foundation of China (31130062, 31070643)Tsinghua University (20121080028)
文摘The mitogen-activated protein kinase (MAPK) p38α is a key regulator in many cellular processes, whose activity is tightly regulated by upstream kinases, phosphatases and other regulators. Transforming growth factor-β activated kinase 1 (TAK1) is an upstream kinase in p38α signaling, and its full activation requires a specific activator, the TAK1-binding protein (TAB1). TAB1 was also shown to be an inducer of p38α's autophosphorylation and/or a substrate driving the feedback control of p38α signaling. Here we determined the complex structure of the unphosphorylated p38α and a docking peptide of TAB1, which shows that the TAB1 peptide binds to the classical MAPK docking groove and induces long-range conformational changes on p38α. Our structural and biochemical analyses suggest that TAB1 is a reasonable substrate of p38α, yet the interaction between the docking peptide and p38α may not be sufficient to trigger trans-autophosphorylation of p38α.
基金the National Natural Science Foundation of China(Nos.81701568,81930041,81571524,81872248,and 91842103)the Zhejiang Provincial Natural Science Foundation of China(Nos.Y15C080001 and Z19H100001)the Zhejiang Provincial Key Laboratory for Immunity and Inflammatory Diseases for its support。
文摘Although microRNA-155(miR-155)is considered a pro-inflammatory mediator,cumulative evidence indicates that it also has anti-inflammatory effects in macrophages and dendritic cells.In this study,we identified the dramatic expression changes of more than half of potential miR-155-targeted genes upon lipopolysaccharide(LPS)stimulation;223 genes were down-regulated and 85 genes were up-regulated,including suppressor of cytokine signaling 1(SOCS1)and transforming growth factor-β-activated kinase 1-binding protein 2(TAB2),two well-known genes involved in miR-155-mediated regulation of the Toll-like receptor 4(TLR4)signaling pathway.We also found that miR-155 acted as an anti-inflammatory mediator in the initial stage of LPS-induced inflammatory response mainly through repressing TAB2 protein translation,and as a proinflammatory mediator by down-regulating SOCS1 in the later stage.Meanwhile,overexpression of TAB23'untranslated region(UTR)in macrophages promoted the development of endotoxin tolerance by competing for binding with miR-155,which resulted in an elevated expression level of SOCS1 protein.These findings provide new insights for understanding the regulatory mechanisms in fine-tuning of LPS-induced innate immune response.
