Zinc finger protein ZBTB20 promotes toll-like receptor-triggered innate immune responses by repressing IκBα gene transcription
Zinc finger protein ZBTB20 promotes toll-like receptor-triggered innate immune responses by repressing IκBα gene transcription
复制标题
DOI：
10.1073/pnas.1301257110
复制
发表时间：
2013-07-02
影响因子：
11.1
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
--
作者：
Liu, Xingguang;Zhang, Peng;Cao, Xuetao
Toll样受体（TLR）信号传导在抵抗入侵病原体的先天性应答中是至关重要的。然而，TLR触发的先天免疫的分子机制需要充分阐明。BTB/POZ家族是一类广泛复杂的转录因子，参与多种生物学过程。然而，很少有报道BTB/POZ蛋白在先天免疫应答中起作用。锌指和含BTB结构域20（ZBTB 20）是BTB/POZ家族的成员，在肝脏中参与神经发生并抑制甲胎蛋白基因转录。然而，ZBTB 20的免疫功能仍然未知。在这里，我们发现骨髓细胞特异性ZBTB 20基因敲除小鼠对内毒素休克和大肠杆菌引起的脓毒症有抵抗力。ZBTB 20缺陷减弱了TLR触发的巨噬细胞中促炎细胞因子和I型IFN的产生，这归因于I κ B α蛋白的较高丰度和NF-κ B活性受损。ChIP和新一代高通量DNA测序结果显示，TLR激活后，ZBTB 20可与I κ B α基因启动子（+ 1 ~+ 60区）特异性结合。ZBTB 20可抑制I kappa B α基因转录，调控I kappa B α蛋白表达，进而促进NF-κ B B活化。因此，需要转录抑制子ZBTB 20通过选择性抑制子I κ B α基因转录来促进TLR信号传导和TLR触发的先天免疫应答的完全激活。
Toll-like receptor (TLR) signaling is critical in innate response against invading pathogens. However, the molecular mechanisms for full activation of TLR-triggered innate immunity need to be fully elucidated. The broad complex tramtrack bric-a-brac/poxvirus and zinc finger (BTB/POZ) family is a class of transcription factors involved in many biological processes. However, few BTB/POZ proteins were reported to function in innate immune response. Zinc finger and BTB domain-containing 20 (ZBTB20), a member of BTB/POZ family, functions in neurogenesis and represses a-fetoprotein gene transcription in liver. However, the immunological functions of ZBTB20 remain unknown. Here, we found that myeloid cell-specific ZBTB20 KO mice were resistant to endotoxin shock and Escherichia coli-caused sepsis. ZBTB20 deficiency attenuated TLR-triggered production of proinflammatory cytokines and type I IFN in macrophages, which attributed to higher abundance of I kappa B alpha protein and impaired activity of NF-kappa B. Furthermore, ChIP and next generation high-throughput DNA sequencing assay showed that ZBTB20 specifically bound to I kappa B alpha gene promoter (+ 1 to + 60 region) after TLR activation. ZBTB20 could inhibit I kappa B alpha gene transcription, govern I kappa B alpha protein expression, and then promote NF-.B activation. Therefore, transcriptional repressor ZBTB20 is needed to promote full activation of TLR signaling and TLR-triggered innate immune response by selectively suppressing the suppressor I kappa B alpha gene transcription.