Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, CO 80206, USA.
J Immunol. 2012 Mar 15;188(6):2905-13. doi: 10.4049/jimmunol.1102595. Epub 2012 Feb 6.
We previously identified Tbc1d23 as a candidate novel regulator of innate immunity using comparative genomics RNA interference screens in Caenorhabditis elegans and mouse macrophages. Using Tbc1d23 knockout mice and macrophages engineered to overexpress Tbc1d23, we now show that Tbc1d23 is a general inhibitor of innate immunity signaling, strongly inhibiting multiple TLR and dectin-signaling pathways. Tbc1d23 likely acts downstream of the TLR-signaling adaptors MyD88 and Trif and upstream of the transcription factor XBP1. Importantly, like XBP1, Tbc1d23 affects the maintenance, but not the initiation, of inflammatory cytokine production induced by LPS. Tbc1d23 acts as a RAB-GAP to regulate innate immunity signaling. Thus, Tbc1d23 exerts its inhibitory effect on innate immunity signaling in a spatiotemporal fashion. The identification of a novel spatiotemporal regulator of innate immunity signaling validates the comparative genomics approach for innate immunity gene discovery.
我们之前使用比较基因组学 RNA 干扰筛选在秀丽隐杆线虫和小鼠巨噬细胞中鉴定出 Tbc1d23 是先天免疫的一个候选新型调控因子。使用 Tbc1d23 敲除小鼠和过表达 Tbc1d23 的巨噬细胞，我们现在表明 Tbc1d23 是先天免疫信号的普遍抑制剂，强烈抑制多种 TLR 和 dectin 信号通路。Tbc1d23 可能作用于 TLR 信号适配器 MyD88 和 Trif 的下游以及转录因子 XBP1 的上游。重要的是，与 XBP1 一样，Tbc1d23 影响 LPS 诱导的炎性细胞因子产生的维持，但不影响其起始。Tbc1d23 作为 RAB-GAP 调节先天免疫信号。因此，Tbc1d23 以时空方式发挥其对先天免疫信号的抑制作用。先天免疫信号新型时空调控因子的鉴定验证了比较基因组学方法在先天免疫基因发现中的有效性。
