Pre-mRNA fate decision by TTP safeguards the fidelity of the inflammatory response

Successful immune responses are dependent on a precisely controlled balance between transcription and mRNA degradation. mRNA decay is driven through RNA-binding proteins (RBP), yet it remains unclear, how and when an individual mRNA molecule is selected for degradation. We investigated this fundamental question by using the anti-inflammatory RBP tristetraprolin (TTP, also known as Zfp36) as a model. Here, we show that TTP determines the fate of its targets concomitantly with their synthesis by binding to the pre-mRNA in the nucleus. Furthermore, we provide evidence that TTP orchestrates the target destabilization via a hierarchical molecular assembly that culminates by the association of mature mRNA with the RNA degradation machinery in the cytoplasm. The early fate decision in the life cycle of a TTP target mRNA prevents the translation of inflammatory mediators, particularly cytokine mRNAs, and promotes efficient cessation of the immune response. Importantly, the TTP homolog ZFP36L1 displays similar characteristics, suggesting a conserved mode of action within the ZFP36 family of RBPs.

有效的免疫应答依赖于转录与mRNA降解之间精准调控的动态平衡。mRNA降解由RNA结合蛋白（RNA-binding protein, RBP）介导，但目前仍不清楚单个mRNA分子是如何、在何时被选择进入降解途径的。本研究以抗炎性RNA结合蛋白tristetraprolin（TTP，亦称Zfp36）为模型，对这一基础科学问题展开探究。研究表明，TTP可通过在细胞核内结合前体mRNA，与靶标mRNA的合成同步决定其命运。此外，本研究提供证据显示，TTP通过层级化的分子组装统筹调控靶标mRNA的去稳定化，最终通过成熟mRNA与细胞质内RNA降解复合物的结合完成该过程。TTP靶标mRNA生命周期中的早期命运决定，可阻断炎性介质（尤其是细胞因子mRNA）的翻译过程，进而促进免疫应答的高效终止。值得注意的是，TTP同源蛋白ZFP36L1具有相似的特性，这表明ZFP36家族RNA结合蛋白存在保守的作用模式。