Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
PLoS One. 2011;6(5):e19829. doi: 10.1371/journal.pone.0019829. Epub 2011 May 17.
The generation of diversity and plasticity of transcriptional programs are key components of effective vertebrate immune responses. The role of Alternative Splicing has been recognized, but it is underappreciated and poorly understood as a critical mechanism for the regulation and fine-tuning of physiological immune responses. Here we report the generation of loss-of-function phenotypes for a large collection of genes known or predicted to be involved in the splicing reaction and the identification of 19 novel regulators of IL-1β secretion in response to E. coli challenge of THP-1 cells. Twelve of these genes are required for IL-1β secretion, while seven are negative regulators of this process. Silencing of SFRS3 increased IL-1β secretion due to elevation of IL-1β and caspase-1 mRNA in addition to active caspase-1 levels. This study points to the relevance of splicing in the regulation of auto-inflammatory diseases.
转录程序多样性和可塑性的产生是脊椎动物有效免疫反应的关键组成部分。可变剪接的作用已被认识到，但作为调节和微调生理免疫反应的关键机制，它还未得到充分的重视和理解。在这里，我们报告了针对大量已知或预测涉及剪接反应的基因的功能丧失表型的产生，并鉴定了 19 种新型调节剂，它们可响应大肠杆菌对 THP-1 细胞的刺激，从而调节 IL-1β 的分泌。其中 12 个基因是 IL-1β 分泌所必需的，而 7 个基因是该过程的负调节剂。SFRS3 的沉默会增加 IL-1β 的分泌，这是由于 IL-1β 和 caspase-1 mRNA 的升高，以及活性 caspase-1 水平的升高。这项研究表明剪接在自身炎症性疾病的调节中具有重要意义。
