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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF-X, Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: WeiQiang Chen

LAB HEAD: Pavel Kovarik

PROVIDER: PXD046381 | Pride | 2025-01-27

REPOSITORIES: pride

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			Action	DRS
	01_LCMS_report.xlsx.xlsx	Xlsx
	01_MaxQuant_txt.zip	Other
	01_cassiopeia_result.zip	Other
	02_LCMS_report.xlsx	Xlsx
	02_MaxQuant_txt.zip	Other

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Cytoplasmic mRNA decay controlling inflammatory gene expression is determined by pre-mRNA fate decision

Project description:The fidelity of immune responses depends 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, destabilizes target mRNAs via a hierarchical molecular assembly. The formation of the assembly 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, while 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 mechanism prevents the translation of excessive and potentially harmful inflammation mediators, irrespective of transcription.

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