Inflammation triggers formation of protein-coding chimeric RNAs in mouse macrophages
Researchers discovered that inflammatory signals cause macrophages to splice together distant genes, creating chimeric mRNAs that encode functional proteins.
A comprehensive pipeline combining Oxford Nanopore direct RNA sequencing, short-read validation, NanoString probes and PCR confirmed the existence of chimeric mRNAs in mouse macrophages, many derived from interchromosomal gene pairs. Hi-C analysis showed that inflammatory stimulation increased CTCF-mediated contacts between the loci of parent genes, facilitating precise trans-splicing without detectable genomic rearrangements.
The most studied fusion linked the pore-forming protein gasdermin D (GSDMD) to a C-terminal segment of Tmem106a, generating a membrane-associated protein that accelerates GSDMD-NT pore assembly and boosts early IL-1β secretion. Mice lacking this chRNA were resistant to LPS-induced lethal sepsis yet exhibited higher bacterial loads after Salmonella infection; conversely, overexpression enhanced bacterial clearance but increased sepsis mortality. These results demonstrate that inflammation-driven chRNA formation expands the functional proteome and modulates host defense and immunopathology.
Why it matters
It shows that immune cells can create new proteins by splicing distant genes, affecting infection outcomes and sepsis risk.
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