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The N6-methyladenosine RNA-binding protein YTHDF1 modulates the translation of TRAF6 to mediate the intestinal immune response.

ABSTRACT: The intestinal invasion of pathogenic microorganisms can have serious health consequences. Recent evidence has shown that the N6-methyladenosine (m6A) mRNA modification is closely associated with innate immunity; however, the underlying mechanism is poorly understood. Here, we examined the function and mechanism of m6A mRNA modification and the YTH domain-containing protein YTHDF1 (YTH N6-methyladenosine RNA-binding protein 1) in the innate immune response against bacterial pathogens in the intestine. Ribo-seq and m6A-seq analyses revealed that YTHDF1 directs the translation of Traf6 mRNA, which encodes tumor necrosis factor receptor-associated factor 6, thereby regulating the immune response via the m6A modification near the transcript's stop codon. Furthermore, we identified a unique mechanism by which the P/Q/N-rich domain in YTHDF1 interacts with the DEAD domain in the host factor DDX60, thereby regulating the intestinal immune response to bacterial infection by recognizing the target Traf6 transcript. These results provide novel insights into the mechanism by which YTHDF1 recognizes its target and reveal YTHDF1 as an important driver of the intestinal immune response, opening new avenues for developing therapeutic strategies designed to modulate the intestinal immune response to bacterial infection.

SUBMITTER: Zong X

PROVIDER: S-EPMC8191762 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Long non-coding RNAs (lncRNAs) were reported to potentially play a regulatory role in the process of myocardial regeneration in the neonatal mouse. N6-methyladenosine (m6A) modification may play a key role in myocardial regeneration in mice and regulates a variety of biological processes through affecting the stability of lncRNAs. However, the map of m6A modification of lncRNAs in mouse cardiac development still remains unknown. We aimed to investigate the differences in the m6A status of lncRNAs during mouse cardiac development and reveal a potential role of m6A modification modulating lncRNAs in cardiac development and myocardial regeneration during cardiac development in mice. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) of the heart tissue in C57BL/6 J mice at postnatal day 1 (P1), P7 and P28 were performed to produce stagewise cardiac lncRNA m6A-methylomes in a parallel timeframe with the established loss of an intrinsic cardiac regeneration capacity and early postnatal development. There were significant differences in the distribution and abundance of m6A modifications in lncRNAs in the P7 vs P1 mice. In addition, the functional role of m6A in regulating lncRNA levels was established for selected transcripts with METTL3 silencing in neonatal cardiomyocytes in vitro. Based on our MeRIP-qPCR experiment data, both lncGm15328 and lncRNA Zfp597, that were not previously associated with cardiac regeneration, were found to be the most differently methylated at P1-P7. These two lncRNAs sponged several miRNAs which further regulated multiple mRNAs, including some of which have previously been linked with cardiac regeneration ability. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed that differential m6A modifications were more enriched in functions and cellular signalling pathways related to cardiomyocyte proliferation. Our data suggested that the m6A modification on lncRNAs may play an important role in the regeneration of myocardium and cardiac development.

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The N6-methyladenosine RNA-binding protein YTHDF1 modulates the translation of TRAF6 to mediate the intestinal immune response.

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