Clarification of LIM protein family-mediated system that regulates innate immune responses.

阐明 LIM 蛋白家族介导的调节先天免疫反应的系统。

• 批准号: 18590480
• 负责人: TANAKA Takashi
• 金额: $ 2.57万
• 依托单位: The Institute of Physical and Chemical Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590480/
• 关键词: LIM proteins; innate immunity; ubiouitin E3 Haase; NF-κB; 樹状細胞

PDLIM2 is a nuclear LIM protein that binds to and inhibits the activity of STAT4 transcription factor. In this study, we have demonstrated that PDLIM2 also negatively regulates the activity of NF-kB transcription factor, acting as a nuclear ubiquitin E3 ligase toward the p65 subunit of NF-KB (Tanaka, et. al., Nat. Immuno1. 8, 584, 2007). PDLIM2 binds to p65 and promotes p65 polyubiquitination through its LIM domain. In addition, PDLIM2 targets p65 to discrete intranuclear compartments called PML nuclear bodies. PML nuclear bodies are nuclear proteolytic centers where proteasomal components are concentrated. Polyubiquitinated p65 is ultimately degraded by proteasome in this compartment. A PDLIM2 mutant lacking the PDZ domain fails to target p65 to nuclear bodies, suggesting that PDLIM2 mediates intranuclear trafficking of p65 through its PDZ domain. PDLIM2 deficiency results in larger amounts of nuclear p65, defective p65 ubiquitination and augmented production of proinflammatory cytokines in response to TLR ligands, such as LPS and CpG-DNA. These findings delineate a novel pathway by which PDLIM2 terminates NF-kB activation through intranuclear sequestration and subsequent degradation. Moreover, we have shown that PDLIM2 can also inhibit both IRF3 and IRF7-mediated transactivation in luciferase assay with IFNIβ or IFNα□promoter-driven reporter construct, respectively. Among LIM protein family, Ril (PDLIM4), elfin (PDLIM1) and ALP (PDLIM3) are the most closely related with PDLIM2Moreover, we have found that these LIM proteins could inhibit NF-KB-mediated transactivation in luciferase assay with reporter containing NF-kB binding site. These findings suggest that LIM proteins are the novel family that negatively regulates signal transductions in immune system.

PDLIM2是一种与STAT4转录因子结合并抑制其活性的核LIM蛋白。在这项研究中，我们已经证明PDLIM2也负向调节NF-kB转录因子的活性，作为NF-kB p65亚基的核泛素E3连接酶（Tanaka等，Nat. Immuno1）。8,584, 2007)。PDLIM2结合p65并通过其LIM结构域促进p65多泛素化。此外，PDLIM2将p65靶向于称为PML核体的离散核内室。PML核体是蛋白酶体成分集中的核蛋白水解中心。多泛素化的p65最终被这个隔室中的蛋白酶体降解。缺乏PDZ结构域的PDLIM2突变体无法将p65靶向到核小体，这表明PDLIM2通过其PDZ结构域介导p65的核内转运。PDLIM2缺乏导致核p65数量增加，p65泛素化缺陷和促炎细胞因子的产生增加，以响应TLR配体，如LPS和CpG-DNA。这些发现描述了PDLIM2通过核内隔离和随后的降解终止NF-kB活化的新途径。此外，在IFNIβ或IFNα□启动子驱动的报告因子构建的荧光素酶实验中，我们已经证明PDLIM2也可以分别抑制IRF3和irf7介导的转激活。在LIM蛋白家族中，Ril （PDLIM4）、elfin （PDLIM1）和ALP （PDLIM3）与pdlim2的关系最为密切。此外，我们在含有NF-kB结合位点的报告蛋白荧光素酶实验中发现，这些LIM蛋白可以抑制NF-kB介导的转激活。这些发现表明，LIM蛋白是免疫系统中负调控信号转导的新家族。

项目成果

PDLIM2-mediated termination of transcription factor NF-kB activation by intranuclear sequestration and degradation fo the p65 subunit.

PDLIM2 介导的通过核内隔离和 p65 亚基降解来终止转录因子 NF-kB 的激活。

• 发表时间: 2007
• 期刊: Nature Immunol. 8(6)
• 作者: T. Tanaka;S. Uematsu;M. Nakahira;T. Tanaka
• 通讯作者: T. Tanaka

Regulation of Signal Transducer and Activator of Transcription Signaling by the Tyrosine Phosphatase

酪氨酸磷酸酶对信号转导器和转录信号激活剂的调节

• 发表时间: 2007
• 期刊: Immunity. 26
• 作者: T. Tanaka;S. Uematsu;M. Nakahira;T. Tanaka;M. Nakahira
• 通讯作者: M. Nakahira

Heat shock proteins regulate PDLIM2-mediated NF-kB

热休克蛋白调节 PDLIM2 介导的 NF-kB

• 发表时间: 2007
• 作者: 田中 貴志;Fujii S;T. Tanaka;T. Tanaka
• 通讯作者: T. Tanaka

p65媒介シグナル伝達の調節剤およびスクリーニング方法

p65介导的信号传导调节剂和筛选方法

• 发表时间: 2007

Gene expression profiles of mouse dendritic cell subsets.

小鼠树突状细胞亚群的基因表达谱。

• 发表时间: 2006
• 期刊: J. Tokyo Med. Univ. 64
• 作者: Shimizu K;Goto A;Fukui K;Taniguchi M;Fujii S;K. Hoshino;M. Saito
• 通讯作者: M. Saito