Bestehorn Annika, von Wirén Julius, Zeiler Christina, Fesselet Jeanne, Didusch Sebastian, Forte Maurizio, Doppelmayer Kevin, Borroni Martina, Le Heron Anita, Scinicariello Sara, Chen WeiQiang, Baccarini Manuela, Pfanzagl Vera, Versteeg Gijs A, Hartl Markus, Kovarik Pavel
Max Perutz Labs, Vienna Biocenter Campus (VBC), Dr.-Bohr-Gasse 9, 1030 Vienna, Austria; University of Vienna, Max Perutz Labs, Department of Microbiology, Immunobiology and Genetics, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria; Vienna Biocenter PhD Program, a Doctoral School of the University of Vienna and Medical University of Vienna, 1030 Vienna, Austria.
Max Perutz Labs, Vienna Biocenter Campus (VBC), Dr.-Bohr-Gasse 9, 1030 Vienna, Austria; University of Vienna, Max Perutz Labs, Department of Microbiology, Immunobiology and Genetics, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria.
Mol Cell. 2025 Feb 20;85(4):742-755.e9. doi: 10.1016/j.molcel.2025.01.001. Epub 2025 Jan 24.
The fidelity of immune responses depends on timely controlled and selective mRNA degradation that is largely driven by RNA-binding proteins (RBPs). It remains unclear whether stochastic or directed processes govern the selection of an individual mRNA molecule for degradation. Using human and mouse cells, we show that tristetraprolin (TTP, also known as ZFP36), an essential anti-inflammatory RBP, destabilizes target mRNAs via a hierarchical molecular assembly. The assembly formation strictly relies on the interaction of TTP with RNA. The TTP homolog ZFP36L1 exhibits similar requirements, indicating a broader relevance of this regulatory program. Unexpectedly, the assembly of the cytoplasmic mRNA-destabilization complex is licensed in the nucleus by TTP binding to pre-mRNA, which we identify as the principal TTP target rather than mRNA. Hence, the fate of an inflammation-induced mRNA is decided concomitantly with its synthesis. This mechanism prevents the translation of excessive and potentially harmful inflammation mediators, irrespective of transcription.
免疫反应的保真度取决于及时受控且具有选择性的mRNA降解，这在很大程度上由RNA结合蛋白（RBP）驱动。目前尚不清楚是随机过程还是定向过程决定了单个mRNA分子的降解选择。利用人类和小鼠细胞，我们发现锌指蛋白36（TTP，也称为ZFP36），一种重要的抗炎RBP，通过分级分子组装使靶标mRNA不稳定。组装的形成严格依赖于TTP与RNA的相互作用。TTP同源物ZFP36L1表现出类似的要求，表明该调控程序具有更广泛的相关性。出乎意料的是，细胞质mRNA去稳定化复合物的组装在细胞核中通过TTP与前体mRNA的结合而被许可，我们将其确定为TTP的主要靶标而非mRNA。因此，炎症诱导的mRNA的命运在其合成时就已决定。这种机制可防止过度且可能有害的炎症介质的翻译，而与转录无关。
