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是一种结合研究和吸入性的核蛋白。 NAT在p65的PDLIM2缺陷中，P65对p65进行了核心。通过核内sequsestration和subygradation的激活，我们表明PDLIM2还可以抑制IFNIβ或IFNIα□启动子驱动的报告者构建体中的3和IRF7介导的激活。 ALP（PDLIM3）与PDLIM2的荧光素酶测定法中的PDLIM2MOREVENTICTARTER-RETORTER与NF-KB结合位点的荧光素酶测定法中，LIM蛋白是在免疫系统中造成信号传递的新家庭。

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

SLIM, a nuclear ubiquitin E3 ligase, terminates NF-κB activation by itssequestration and degradation.

SLIM 是一种核泛素 E3 连接酶，通过隔离和降解来终止 NF-κB 的激活。

• 发表时间: 2006
• 作者: Shimizu;K.;Fujii;S.;T. Tanaka
• 通讯作者: T. Tanaka

「研究成果報告書概要(和文)」より

摘自《研究结果报告摘要（日文）》

• 发表时间: 2005
• 作者: Kawauchi;et. al.;Nishimura et al.;Dezawa et al.;Yoshizawa et al.;星野 幹雄;星野 幹雄
• 通讯作者: 星野 幹雄

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

SLIM, a nuclear ubiquitin E3 ligase, terminates NF-kB activation by its sequestration and degiadation

SLIM 是一种核泛素 E3 连接酶，通过隔离和去连接终止 NF-kB 激活

• 发表时间: 2006
• 作者: Shimizu;K;Fujii S.;T. Tanaka
• 通讯作者: T. Tanaka