hnRNPM protects against the dsRNA-mediated interferon response by repressing LINE-associated cryptic splicing.

RNA splicing is pivotal in post-transcriptional gene regulation, yet the exponential expansion of intron length in humans poses a challenge for accurate splicing. Here, we identify hnRNPM as an essential RNA-binding protein that suppresses cryptic splicing through binding to deep introns, maintaining human transcriptome integrity. Long interspersed nuclear elements (LINEs) in introns harbor numerous pseudo splice sites. hnRNPM preferentially binds at intronic LINEs to repress pseudo splice site usage for cryptic splicing. Remarkably, cryptic exons can generate long dsRNAs through base-pairing of inverted ALU transposable elements interspersed among LINEs and consequently trigger an interferon response, a well-known antiviral defense mechanism. Significantly, hnRNPM-deficient tumors show upregulated interferon-associated pathways and elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity by repressing cryptic splicing and suggest that targeting hnRNPM in tumors may be used to trigger an inflammatory immune response, thereby boosting cancer surveillance.

The essential role of mRNA degradation in understanding and engineering E. coli metabolism.

Metabolic engineering strategies are crucial for the development of bacterial cell factories with improved performance. Until now, optimal metabolic networks have been designed based on systems biology approaches integrating large-scale data on the steady-state concentrations of mRNA, protein and metabolites, sometimes with dynamic data on fluxes, but rarely with any information on mRNA degradation. In this review, we compile growing evidence that mRNA degradation is a key regulatory level in E. coli that metabolic engineering strategies should take into account. We first discuss how mRNA degradation interacts with transcription and translation, two other gene expression processes, to balance transcription regulation and remove poorly translated mRNAs. The many reciprocal interactions between mRNA degradation and metabolism are also highlighted: metabolic activity can be controlled by changes in mRNA degradation and in return, the activity of the mRNA degradation machinery is controlled by metabolic factors. The mathematical models of the crosstalk between mRNA degradation dynamics and other cellular processes are presented and discussed with a view towards novel mRNA degradation-based metabolic engineering strategies. We show finally that mRNA degradation-based strategies have already successfully been applied to improve heterologous protein synthesis. Overall, this review underlines how important mRNA degradation is in regulating E. coli metabolism and identifies mRNA degradation as a key target for innovative metabolic engineering strategies in biotechnology.