Absence of SHIP-1 Results in Constitutive Phosphorylation of Tank-Binding Kinase 1 and Enhanced TLR3-Dependent IFN-β Production
Absence of SHIP-1 Results in Constitutive Phosphorylation of Tank-Binding Kinase 1 and Enhanced TLR3-Dependent IFN-β Production
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DOI：
10.4049/jimmunol.0902589
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发表时间：
2010-03-01
影响因子：
4.4
通讯作者：
Jefferies, Caroline A.
中科院分区：
文献类型：
--
作者：
Gabhann, Joan Ni;Higgs, Rowan;Jefferies, Caroline A.
自身免疫性疾病，如系统性红斑狼疮和类风湿性关节炎，是由于对自身抗原的耐受性丧失和I型IFN和炎性细胞因子的过度产生所引起的免疫介导的损伤。我们已经确定肌醇5'磷酸酶SHIP-1是TLR 3诱导的I型IFN产生的负调节因子。SHIP-1缺陷的巨噬细胞显示增强的TLR诱导的IFN-β产生，并且SHIP-1的过表达负调节TLR 3及其衔接子（含有Toll/IL-1受体结构域的衔接子诱导IFN-β）诱导IFN-β启动子活性的能力，表明SHIP-1负调节TLR诱导的IFN-β产生。对IFN-β途径的进一步研究表明TANK结合激酶1（TBK 1）是SHIP-1的靶点。关键的是，在没有SHIP-1的情况下，TBK 1。似乎在未刺激的细胞和TLR 3刺激后都被过度磷酸化。此外，TBK 1似乎与SHIP-1缺陷细胞中含有Toll/IL-1受体结构域的衔接子诱导IFN-β和TNFR相关因子3组成性相关，而在野生型细胞中，这种相关性在TLR 3刺激后是可诱导的。为了支持SHIP-I在调节复合物形成中的作用，共聚焦显微镜显示，与野生型对照相比，在SHIP-1缺陷细胞中TBK 1在细胞中的分布显著改变，观察到更突出的内体染色。综上所述，我们的研究结果表明SHIP-1通过调节TBK 1的定位和活性，作为TLR 3下游IFN-β产生的关键负调节因子。免疫学杂志，2010，184：2314-2320。
Autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, result from a loss of tolerance to self-antigens and immune-mediated injury precipitated by the overproduction of type I IFN and inflammatory cytokines. We have identified the inositol 5' phosphatase SHIP-1 as a negative regulator of TLR3-induced type I IFN production. SHIP-1-deficient macrophages display enhanced TLR-induced IFN-beta production, and overexpression of SHIP-1 negatively regulates the ability of TLR3 and its adaptor, Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta, to induce IFN-beta promoter activity, indicating that SHIP-1 negatively regulates TLR-induced IFN-beta production. Further dissection of the IFN-beta pathway implicates TANK-binding kinase 1 (TBK1) as the target for SHIP-1. Critically, in the absence of SHIP-1, TBK1. appears to be hyperphosphorylated both in unstimulated cells and following TLR3 stimulation. In addition, TBK1 appears to be constitutively associated with Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta and TNFR-associated factor 3 in SHIP-1 deficient cells, whereas in wild-type cells this association is inducible following TLR3 stimulation. In support of a role for SHIP-I in regulating complex formation, confocal microscopy demonstrates that TBK1 distribution in the cell is significantly altered in SHIP-1-deficient cells, with more prominent endosomal staining observed, compared with wild-type controls. Taken together, our results point to SHIP-1 as a critical negative regulator of IFN-beta production downstream of TLR3 through the regulation of TBK1 localization and activity. The Journal of Immunology, 2010, 184: 2314-2320.