A novel Zinc finger protein, ZCCHC11, interacts with TIFA and modulates TLR signaling
A novel Zinc finger protein, ZCCHC11, interacts with TIFA and modulates TLR signaling
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新型锌指蛋白 ZCCHC11 与 TIFA 相互作用并调节 TLR 信号转导
DOI：
10.1016/j.bbrc.2006.04.006
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发表时间：
2006-06-09
影响因子：
3.1
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Minoda, Yasumasa;Saeki, Kazuko;Yoshimura, Akihiko
Toll样受体（TLR）作为微生物病原体的传感器在先天免疫应答中发挥重要作用。TLR通过包括肿瘤坏死因子相关因子6（TRAF 6）的衔接蛋白的募集来传递信号。其介导I κ B激酶（IKK）的活化。TIFA（具有叉头相关（FHA）结构域的TRAF相互作用蛋白）已被证明与TRAF 6结合并通过促进TRAF 6的寡聚化和泛素连接酶活性来激活IKK。FHA结构域优先结合其靶标中的磷酸-苏氨酸残基。这里.我们鉴定了一种新的锌指蛋白ZCCHC 11，其与来自巨噬细胞系的磷蛋白的TIFA相互作用。RAW 264.7，通过使用GST-TIFA亲和纯化和质谱分析。通过检索EST数据库。我们发现了200 kDa的全长形式（ZCCHC 11 L）。ZCCHC 11 L主要定位于细胞核，但在LPS刺激下移位至细胞质并与TIFA结合。ZCCHC 11的过表达和siRNA敲低表明ZCCHC 11作为TLR介导的NF-κ B活化的负调节因子发挥作用。包括CCHC型锌指基序的N-末端区域（ZCCHC 11 S）足以抑制NF-κ B。我们认为ZCCHC 11是一种独特的TLR信号调节因子。其在LPS处理后与TIFA相互作用并抑制NF-κ B的TRAF 6依赖性活化。(c)2006年爱思唯尔公司All rights reserved.
Toll-like receptors (TLRs) play an important role as a sensor of microbial pathogens in the innate immune response. TLRs transmit signals through the recruitment of adaptor proteins including tumor necrosis factor-associated factor 6 (TRAF6). which mediates the activation of I kappa B kinase (IKK). TIFA (TRAF-interacting protein with a forkhead-associated (FHA) domain) has been shown to bind to TRAF6 and activate IKK by promoting the oligomerization and Ubiquitin-ligase activity of TRAF6. FHA domains preferentially bind to phospho-threonine residues in their targets. Here. we identified a novel zinc finger protein, ZCCHC 11, that interacts with TIFA from phosphoproteins of a macrophage cell line. RAW 264.7, by Using affinity purification with GST-TIFA and mass spectrometric analysis. By a search of the EST database. we found a 200 kDa full-length form (ZCCHC11L). ZCCHC11L\vas mostly located to the nucleus, but translocated into the cytoplasm in response to LPS and bound to TIFA. Overexpression and knockdown by siRNA indicated that ZCCHC11 functions as a negative regulator of TLR-mediated NF-kappa B activation. The N-terminal region (ZCCHC11S) including CCHC-type Zn-finger motif was sufficient for Suppression of NF-kappa B. We propose that ZCCHC11 is a unique TLR signal regulator. which interacts with TIFA after LPS treatment and suppresses the TRAF6-dependent activation of NF-kappa B. (c) 2006 Elsevier Inc. All rights reserved.