Wynne Claire, Lazzari Elisa, Smith Siobhán, McCarthy Eoghan M, Ní Gabhann Joan, Kallal Lara E, Higgs Rowan, Greco Angela, Cryan Sally Ann, Biron Christine A, Jefferies Caroline A
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland; School of Biological Sciences, Dublin Institute of Technology, Dublin, Ireland.
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
PLoS One. 2014 Jul 7;9(7):e101503. doi: 10.1371/journal.pone.0101503. eCollection 2014.
In recent years members of the tripartite motif-containing (TRIM) family of E3 ubiquitin ligases have been shown to both positively and negatively regulate viral defence and as such are emerging as compelling targets for modulating the anti-viral immune response. In this study we identify TRIM68, a close homologue of TRIM21, as a novel regulator of Toll-like receptor (TLR)- and RIG-I-like receptor (RLR)-driven type I IFN production. Proteomic analysis of TRIM68-containing complexes identified TRK-fused gene (TFG) as a potential TRIM68 target. Overexpression of TRIM68 and TFG confirmed their ability to associate, with TLR3 stimulation appearing to enhance the interaction. TFG is a known activator of NF-κB via its ability to interact with inhibitor of NF-κB kinase subunit gamma (IKK-γ) and TRAF family member-associated NF-κB activator (TANK). Our data identifies a novel role for TFG as a positive regulator of type I IFN production and suggests that TRIM68 targets TFG for lysosomal degradation, thus turning off TFG-mediated IFN-β production. Knockdown of TRIM68 in primary human monocytes resulted in enhanced levels of type I IFN and TFG following poly(I:C) treatment. Thus TRIM68 targets TFG, a novel regulator of IFN production, and in doing so turns off and limits type I IFN production in response to anti-viral detection systems.
近年来，E3泛素连接酶的含三方基序（TRIM）家族成员已被证明既能正向调节也能负向调节病毒防御，因此正成为调节抗病毒免疫反应的极具吸引力的靶点。在本研究中，我们鉴定出TRIM21的紧密同源物TRIM68，它是Toll样受体（TLR）和视黄酸诱导基因I样受体（RLR）驱动的I型干扰素产生的新型调节因子。对含TRIM68复合物的蛋白质组学分析确定TRK融合基因（TFG）为潜在的TRIM68靶点。TRIM68和TFG的过表达证实了它们相互结合的能力，TLR3刺激似乎增强了这种相互作用。TFG通过与核因子κB抑制激酶亚基γ（IKK-γ）和TRAF家族成员相关的核因子κB激活剂（TANK）相互作用，是已知的核因子κB激活剂。我们的数据确定了TFG作为I型干扰素产生的正向调节因子的新作用，并表明TRIM68将TFG靶向溶酶体降解，从而关闭TFG介导的IFN-β产生。在原代人单核细胞中敲低TRIM68导致在聚肌胞苷酸（poly(I:C)）处理后I型干扰素和TFG水平升高。因此，TRIM68靶向TFG（一种干扰素产生的新型调节因子），并通过这种方式在响应抗病毒检测系统时关闭并限制I型干扰素的产生。
