# The RNA methyltransferase NSUN2 catalyzes 5-methylcytosine (m5C) on IL1B mRNA to promote transcript stability

## TL;DR

This study shows that the enzyme NSUN2 adds a specific RNA modification that stabilizes a key inflammation-related gene, potentially offering new ways to treat inflammatory diseases.

## Contribution

The study identifies NSUN2-mediated m5C modification as a novel regulator of inflammation through stabilization of IL1B mRNA.

## Key findings

- NSUN2 catalyzes m5C modification on IL1B mRNA, promoting its stability.
- Nsun2 deficiency reduces inflammation in systemic and local inflammatory models.
- m5C modifications are recognized by YBX1, enhancing IL1B expression and inflammation.

## Abstract

Among the plethora of RNA modifications, 5-methylcytosine (m5C) has held substantial roles in some biological processes, yet its impact on inflammation remains largely uncharted. Here, we reported an m5C-related epitranscriptomic regulatory axis in inflammatory pathogenesis. Bacterial lipopolysaccharides (LPS) challenge induces marked elevation in RNA m5C abundance as well as the expression of NOP2/Sun RNA methyltransferase 2 (NSUN2), an essential enzyme catalyzing m5C modification. Nsun2 deficient mice showed significantly reduced inflammatory response in the models of systemic inflammation and local pulpitis compared with wild-type control mice. Mechanistically, NSUN2 installs m5C modifications on interleukin 1 beta (IL1B) mRNA. These modifications are selectively recognized by the m5C reader Y-box binding protein 1 (YBX1), thereby enhancing transcript stability and promoting substantial elevation of IL1B, which might further drive inflammation cascades. Our research highlights a pivotal role of NSUN2-mediated m5C RNA modification in regulating inflammatory responses, offering fresh perspectives for the treatment of inflammatory diseases.