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mRNA 3ʹUTR length matters: alternative polyadenylation shapes autophagy and inflammatory responses in macrophages

Cellular & Molecular Immunology volume 22, pages 336–338 (2025)Cite this article

The Original Article was published on 13 November 2024

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In recent years, posttranscriptional cellular processes such as alternative splicing, messenger RNA (mRNA) decay and translational control have emerged as important regulatory layers required for fine-tuning the inflammatory response in coordination with transcriptional regulation. However, among these post-transcriptional mechanisms, very little is known regarding the role of alternative polyadenylation (APA), a process that generates transcripts with different 3ʹ ends, in modulating gene expression during inflammation. In a paper published on this topic, Chen and coworkers provided evidence indicating that alternative polyadenylation promotes macrophage inflammatory functions by modulating the expression of genes involved in the autophagy pathway [1]. These results reveal a new gene expression regulatory mechanism that shapes protein output during macrophage activation and could be implicated in many human inflammatory diseases.

APA can be regulated through changes in the abundance of core factors of the cleavage and polyadenylation machinery or through unrelated RNA binding proteins interacting with cis-acting RNA elements near polyadenylation signal sequences. Among the core factors, Nudt21 (also known as CPSF5 or CFIm25) is part of the mammalian cleavage factor I protein complex (CFIm). Within CFIm, Nudt21 is able to directly interact with the pre-mRNA on “UGUA” sequence motifs enriched in the 3′UTR of a subset of cellular transcripts near polyadenylation signal sequences and is also able to recruit the CPSF complex to the RNA polymerase II C-terminal domain [7]. Although the precise mechanism is not completely understood, the presence of two or more UGUA sites flanking a PAS facilitates Nudt21-dependent skipping, favoring the use of a distal PAS and generating an mRNA with a longer 3′UTR (Fig. 1C). Accordingly, Nudt21 downregulation typically results in the shortening of mRNAs containing proximal polyadenylation signal sequences flanked by UGUA sequences [8].

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Fig. 1
Fig. 2

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Funding

Work in EPR’s laboratory is supported by the European Research Council (ERC-StG-LS6-805500) under the European Union's Horizon 2020 research and innovation programs as well as the ATIP-Avenir program.

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  1. Laboratoire de Biologie et Modelisation de la Cellule, Ecole Normale Superieure de Lyon, CNRS, UMR 5239, Inserm, U1293, Universite Claude Bernard Lyon 1, 46 allée d’Italie, F-69364, Lyon, France

    Wenjun Cai & Emiliano P. Ricci

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  1. Wenjun Cai
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Correspondence to Emiliano P. Ricci.

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Cai, W., Ricci, E.P. mRNA 3ʹUTR length matters: alternative polyadenylation shapes autophagy and inflammatory responses in macrophages. Cell Mol Immunol 22, 336–338 (2025). https://doi.org/10.1038/s41423-024-01252-9

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