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

Abstract

ABSTRACTThe fidelity of immune responses is dependent on a timely controlled and selective mRNA degradation that is largely driven by RNA-binding proteins (RBPs). It remains unclear whether the selection of an individual mRNA molecule for degradation is governed by stochastic or directed processes. Here, we show that tristetraprolin (TTP, also known as ZFP36), an essential anti-inflammatory RBP, destabilized the target mRNA via a hierarchical molecular assembly. The assembly formation is strictly reliant on TTP interaction 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 while mature cytoplasmic mRNA does not constitute a de novo TTP target. Hence, the fate of an inflammation-induced mRNA is decided concomitantly with its synthesis. This fate decision mechanism prevents the translation of superfluous and potentially harmful inflammation mediators, and ensures an efficient cessation of the immune response irrespective of transcriptional activity.