Themis2/ICB1 is a signaling scaffold that selectively regulates macrophage Toll-like receptor signaling and cytokine production.
Themis2/ICB1 is a signaling scaffold that selectively regulates macrophage Toll-like receptor signaling and cytokine production.
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DOI：
10.1371/journal.pone.0011465
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发表时间：
2010-07-13
期刊：
影响因子：
3.7
通讯作者：
Wait R
中科院分区：
文献类型：
--
作者：
Peirce MJ;Brook M;Morrice N;Snelgrove R;Begum S;Lanfrancotti A;Notley C;Hussell T;Cope AP;Wait R
胸腺细胞表达的参与选择1的分子（Themis 1，SwissProt登录号Q8 BGW 0）是最近表征的新蛋白质家族的创始成员。该家族的第二个成员Themis 2（Q91 YX 0），也称为ICB 1（与基底膜1接触时诱导），尽管微阵列和EST数据库报告了Themis 2 mRNA在B细胞和巨噬细胞中的表达，但在蛋白质水平上仍未报道。在这里，我们首次发现Themis 2蛋白，并表明它作为巨噬细胞信号传导支架，对RAW 264.7巨噬细胞中的TLR反应发挥受体，介体和信号传导途径特异性作用。Themis 2过表达增强LPS诱导的TNF产生，但不增强IL-6或考克斯-2，也不增强TLR 2配体（PAM 3）或TLR 3配体（poly I∶C）诱导的TNF产生。此外，LPS诱导的MAP激酶ERK和p38的活化在过表达Themis 2的细胞中增强，而JNK、IRF 3或NF-κB p65的活化不受影响。通过RNA干扰耗尽Themis 2蛋白抑制LPS诱导的原代人巨噬细胞中TNF的产生，证明在该事件中需要Themis 2。Themis 2在LPS刺激后可诱导酪氨酸磷酸化，并与林恩激酶（P25911）、Rho鸟嘌呤核苷酸交换因子Vav（P27870）和衔接蛋白Grb 2（Q60631）相互作用。酪氨酸660或富含脯氨酸的序列（PPPRPPK）的突变同时中断了这种复合物，并降低了约50%的Themis 2促进LPS诱导的TNF产生的能力。最后，Themis 2蛋白的表达诱导巨噬细胞的发展过程中，从小鼠骨髓前体细胞，并调节炎症刺激在体外和体内。我们假设Themis 2可能构成了巨噬细胞炎症反应的一个新的生理控制点。
Thymocyte expressed molecule involved in selection 1 (Themis1, SwissProt accession number Q8BGW0) is the recently characterised founder member of a novel family of proteins. A second member of this family, Themis2 (Q91YX0), also known as ICB1 (Induced on contact with basement membrane 1), remains unreported at the protein level despite microarray and EST databases reporting Themis2 mRNA expression in B cells and macrophages. Here we characterise Themis2 protein for the first time and show that it acts as a macrophage signalling scaffold, exerting a receptor-, mediator- and signalling pathway-specific effect on TLR responses in RAW 264.7 macrophages. Themis2 over-expression enhanced the LPS-induced production of TNF but not IL-6 or Cox-2, nor TNF production induced by ligands for TLR2 (PAM3) or TLR3 (poly I∶C). Moreover, LPS-induced activation of the MAP kinases ERK and p38 was enhanced in cells over-expressing Themis2 whereas the activation of JNK, IRF3 or NF-κB p65, was unaffected. Depletion of Themis2 protein by RNA inteference inhibited LPS-induced TNF production in primary human macrophages demonstrating a requirement for Themis2 in this event. Themis2 was inducibly tyrosine phosphorylated upon LPS challenge and interacted with Lyn kinase (P25911), the Rho guanine nucleotide exchange factor, Vav (P27870), and the adaptor protein Grb2 (Q60631). Mutation of either tyrosine 660 or a proline-rich sequence (PPPRPPK) simultaneously interrupted this complex and reduced by approximately 50% the capacity of Themis2 to promote LPS-induced TNF production. Finally, Themis2 protein expression was induced during macrophage development from murine bone marrow precursors and was regulated by inflammatory stimuli both in vitro and in vivo. We hypothesise that Themis2 may constitute a novel, physiological control point in macrophage inflammatory responses.
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DOI：
10.1126/science.1179050
发表时间：
2009-10-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Amit I;Garber M;Chevrier N;Leite AP;Donner Y;Eisenhaure T;Guttman M;Grenier JK;Li W;Zuk O;Schubert LA;Birditt B;Shay T;Goren A;Zhang X;Smith Z;Deering R;McDonald RC;Cabili M;Bernstein BE;Rinn JL;Meissner A;Root DE;Hacohen N;Regev A
通讯作者：
Regev A
影响因子：
20.3
作者：
Guha, M;O'Connell, MA;Mackman, N
通讯作者：
Mackman, N
DOI：
10.1016/j.jsbmb.2007.12.007
发表时间：
2008-03-01
影响因子：
4.1
作者：
Bollmann, Julia;Ortmann, Olaf;Treeck, Oliver
通讯作者：
Treeck, Oliver
影响因子：
4.8
作者：
Lock, LS;Royal, I;Park, M
通讯作者：
Park, M
影响因子：
5.3
作者：
Brook, M;Tchen, CR;Clark, AR
通讯作者：
Clark, AR