The RNA binding protein, HNRNPA2B1, regulates IFNG signaling in macrophages

Abstract

Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) is a well known RNA binding protein but the mechanisms by which it contributes to innate immune gene regulation are poorly understood. Here we report that HNRNPA2B1 functions in macrophages to regulate IFNG (IFN-γ) signaling through alternative splicing of the IFNG receptor. Specific deletion of HNRNPA2B1 in macrophages resulted in altered cytokine responses in both an endotoxic shock model and following Salmonella infection. Interestingly, while HNRNPA2B1 can function as a viability gene, we observed increased macrophage and neutrophil numbers in the KO mice following LPS induced endotoxic shock. We also discovered that HNRNPA2B1 restricts replication of Salmonella enterica in vivo. Mechanistically, loss of HNRNPA2B1 resulted in an increase in NGO transcripts, which lack a start codon, of the IFNG receptor (Ifngr) leading to lower expression of the receptor at the cell surface impacting the downstream IFNG signaling cascade. Collectively, our data highlight an important role for HNRNPA2B1 in regulating IFNG signaling and restricting intracellular bacterial pathogens in macrophages.

Analyzing the Effects of Single Nucleotide Polymorphisms on hnRNPA2/B1 Protein Stability and Function: Insights for Anticancer Therapeutic Design

“…To our knowledge, this is the first study trying to find and analyze the nonsynonymous SNPs at the protein–RNA interface, leading to a disruption of the cell’s vital functions, such as alternative splicing. Indeed, A2B1 has been found to regulate IFN-γ signaling in macrophages through alternative splicing of the IFN-γ receptor A2B1 also regulates the alternative splicing of BIRC5 to promote gastric cancer progression .…”

“…Indeed, A2B1 has been found to regulate IFN-γ signaling in macrophages through alternative splicing of the IFN-γ receptor. 10 A2B1 also regulates the alternative splicing of BIRC5 to promote gastric cancer progression. 11 If hnRNPA2B1 does not bind to RNA, then it could potentially affect the splicing of BIRC5 and other genes, which could have implications for disease progression.…”