RNA-binding protein hnRNP UL1 binds κB sites to attenuate NF-κB-mediated inflammation

Abstract

Heterogeneous nuclear ribonucleoproteins (hnRNPs), a family of RNA-binding proteins, play important roles in various biological processes. However, the roles of hnRNPs members in immunity and inflammation remain to be fully understood. By a functional screening for hnRNPs members in LPS-stimulated macrophage inflammatory response, we identified hnRNP UL1 as a negative regulator of NF-κB-mediated inflammation. hnRNP UL1 constrains NF-κB-triggered transcriptional expression of pro-inflammatory cytokines in response to innate stimuli. Perturbation of hnRNP UL1 enhanced pro-inflammatory cytokine production in macrophages. In vivo deficiency of hnRNP UL1 increased the pro-inflammatory cytokine production once challenged with LPS. Accordingly, the expression of hnRNP UL1 decreased in peripheral blood mononuclear cells of rheumatoid arthritis patients. Mechanistically, hnRNP UL1 competes with NF-κB to bind κB sites to constrain the magnitude and duration of inflammatory response. Meanwhile, the broadly and dynamically binding of hnRNP UL1 on the target genes' promoter during inflammatory response is unraveled. Our study adds new insight into the functions of hnRNPs in NF-κB-mediated inflammation, proposing a potential therapeutic strategy for controlling inflammatory autoimmune diseases.

Keywords: Inflammation; Interleukin-6; Macrophage; NF-κB; Rheumatoid arthritis; hnRNP UL1.