Latest discoveries

Publication date: 02/09/2026

Authors: Venezia O, Kane H, Du G, Coughlan HD, Johanson TM, Wang H, Tilstam P, Kazer SW, Gunner G, Hoagland DA, Basavappa MG, Ravichandran K, Ada E, Zhakyp A, Kumar S, Duizer C, Searle O, Provido CG, Joannas L

Journal: Nature

Commentary: This study shows that mammalian cells can generate functional proteins through regulated fusion of mRNAs transcribed from different genes. Using long-read direct RNA sequencing together with short-read RNA-seq, NanoString, PCR and Sanger sequencing, the authors identified thousands of candidate chimeric RNAs (chRNAs) in mouse macrophages, with expression regulated by inflammatory state. They focused on Gsdmd-Tmem106a, a chRNA strongly induced by inflammatory stimulation and also detected in macrophages during infection. Genomic PCR excluded a detectable DNA translocation, while spliceosome inhibition and U1 depletion supported an RNA-level trans-splicing mechanism. Hi-C experiments further showed that inflammation increases CTCF-dependent contacts between chRNA parent loci, suggesting that 3D genome organization contributes to their formation.

Importantly, Gsdmd-Tmem106a is not merely an RNA species: it encodes a stable fusion protein containing the GSDMD-derived region and a novel C-terminal sequence translated out of frame from Tmem106a. GSDMD–TMEM106A localizes to the plasma membrane and cooperates with canonical GSDMD N-terminal fragments to accelerate membrane pore formation and IL-1β release. Loss of the fusion protein protects mice from lethal LPS-induced sepsis but compromises antibacterial defence, whereas increased expression enhances antibacterial protection while worsening sepsis pathology. Overall, the paper expands the concept of mammalian transcript and protein diversity beyond conventional cis-splicing and identifies regulated chimeric mRNA formation as a functional component of inflammatory immunity.

Commented by: Lisastella Morinelli

DOI: https://doi.org/10.1038/s41586-026-10982-x