1 Department of Immunology, Institute for Immunobiology, Shanghai Medical College of Fudan University , Shanghai, P.R. China .
J Interferon Cytokine Res. 2013 Oct;33(10):578-87. doi: 10.1089/jir.2012.0170. Epub 2013 May 9.
Tripartite motif (TRIM) 22 plays an important role in interferons (IFNs)-mediated antiviral activity. We previously demonstrated that interferon regulatory factor-1 (IRF-1) played a central role in IFN-γ-induced TRIM22 expression via binding to a special cis-element named 5' extended IFN-stimulating response element (5'eISRE). In this study, we sought to identify the signaling pathways involved in TRIM22 induction by IFN-γ. By using various pharmacological inhibitors, it was found that the activity of tyrosine kinase and phosphatidylcholine-phospholipase C (PC-PLC), but not phosphatidylinositol-phospholipase C (PI-PLC) and phospholipase D (PLD), was required for IFN-γ-induced TRIM22 expression in HepG2 cells. Tyrosine kinase Janus kinase (JAK), not SRC and PYK2, played an indispensable role in TRIM22 induction. Inhibition of protein kinase C (PKC) activity also significantly attenuated IFN-γ induction of TRIM22. Although treatment with IFN-γ resulted in the stimulation of mitogen-activated protein kinases (MAPKs) (p38, ERK, and JNK) and pI3K/Akt/mTOR pathways in HepG2 cells, the inhibition of their activity did not affect IFN-γ-stimulated TRIM22 expression. Further studies showed that overexpression of JAK1 and PKCα activated TRIM22 promoter activity in a 5'eISRE-dependent manner, and inhibition of not only JAK but also PC-PLC/PKC pathways significantly attenuated IFN-γ-induced IRF-1 expression in HepG2 cells. Taken together, these data indicated that IFN-γ induced TRIM22 expression via activation of JAK and PC-PLC/PKC signaling pathways, which involved the cis-element 5'eISRE and the transactivator IRF-1.
三结构域蛋白 22（TRIM22）在干扰素（IFNs）介导的抗病毒活性中发挥重要作用。我们之前的研究表明，干扰素调节因子-1（IRF-1）通过与一个特殊的顺式元件（称为 5'扩展干扰素刺激反应元件（5'eISRE））结合，在 IFN-γ诱导的 TRIM22 表达中发挥核心作用。在这项研究中，我们试图确定参与 IFN-γ诱导 TRIM22 的信号通路。通过使用各种药理学抑制剂，发现酪氨酸激酶和磷脂酰胆碱-磷脂酶 C（PC-PLC）的活性，但不是磷脂酰肌醇-磷脂酶 C（PI-PLC）和磷脂酶 D（PLD）的活性，对于 HepG2 细胞中 IFN-γ诱导的 TRIM22 表达是必需的。酪氨酸激酶 Janus 激酶（JAK），而不是 SRC 和 PYK2，在 TRIM22 诱导中发挥不可或缺的作用。蛋白激酶 C（PKC）活性的抑制也显著减弱了 IFN-γ诱导的 TRIM22 表达。虽然 IFN-γ处理导致 HepG2 细胞中丝裂原激活的蛋白激酶（MAPKs）（p38、ERK 和 JNK）和 pI3K/Akt/mTOR 通路的刺激，但抑制其活性并不影响 IFN-γ刺激的 TRIM22 表达。进一步的研究表明，JAK1 和 PKCα 的过表达以 5'eISRE 依赖性方式激活 TRIM22 启动子活性，不仅抑制 JAK 而且抑制 PC-PLC/PKC 通路显著减弱了 HepG2 细胞中 IFN-γ诱导的 IRF-1 表达。总之，这些数据表明，IFN-γ 通过激活 JAK 和 PC-PLC/PKC 信号通路诱导 TRIM22 表达，该通路涉及顺式元件 5'eISRE 和反式激活因子 IRF-1。
