# TLR-induced STK25 activation promotes IRF5-mediated inflammation

## TL;DR

This study identifies STK25 as a new regulator of inflammation by activating IRF5, a key protein in immune responses, through phosphorylation.

## Contribution

STK25 is newly identified as a kinase that modulates TLR-induced IRF5 activity via phosphorylation.

## Key findings

- STK25 phosphorylates IRF5 at Thr265, promoting its transcriptional activation.
- STK25 autophosphorylates in response to multiple TLR triggers.
- STK25 deficiency reduces IRF5 nuclear translocation and cytokine production in immune cells.

## Abstract

The transcription factor IRF5 functions as a master regulator of innate and adaptive immunity and the STK25 kinase was identified as a new modulator of TLR-induced IRF5 transcriptional activity.

The transcription factor interferon regulatory factor 5 (IRF5) functions as an important mediator of the inflammatory response downstream of MyD88-dependent TLRs. Whereas dysregulation of IRF5 activity has been implicated in the development of numerous autoimmune diseases including systemic lupus erythematosus, the factors that modulate TLR-induced IRF5 post-translational modifications are poorly understood. The focus of this study was to identify novel kinases in TLR-MyD88-IRF5 signaling. We performed a kinome-wide siRNA screen in human THP-1 monocytic cells and identified serine/threonine protein kinase 25 (STK25) as a positive regulator of pro-inflammatory cytokine production via phosphorylation of IRF5 at Thr265, leading to IRF5 transcriptional activation. We further found that STK25 undergoes autophosphorylation in response to multiple TLR triggers. Findings were validated in Stk25-deficient primary immune cells revealing a significant attenuation in R848-induced IRF5 nuclear translocation and pro-inflammatory cytokine production. Finally, we detected increased levels of STK25 autophosphorylation in immune cells from systemic lupus erythematosus donors compared with healthy controls. These findings implicate STK25 as a new regulator of TLR7/8 signaling through the modulation of IRF5 activation.