HuR Promotes miRNA-Mediated Upregulation of NFI-A Protein Expression in MDSCs During Murine Sepsis
Myeloid-derived suppressor cells (MDSCs) contribute to high mortality rates during sepsis, but how sepsis induces MDSCs is unclear. Previously we reported that microRNA (miR)-21 and miR-181b reprogram MDSCs in septic mice by increasing levels of DNA binding transcription factor, nuclear factor 1 (NFI-A). Here, we provide evidence that miR-21 and miR-181b stabilize NFI-A mRNA and increase NFI-A protein levels by recruiting RNA-binding proteins HuR and Ago1 to its 3′ untranslated region (3′UTR). We also find that the NFI-A GU-rich element (GRE)-binding protein CUGBP1 counters miR-21 and miR-181b dependent NFI-A mRNA stabilization and decreases protein production by replacing 3′UTR bound Ago1 with Ago2. We confirmed the miR-21 and miR-181b dependent reprogramming pathway in MDSCs transfected with a luciferase reporter construct containing an NFI-A 3′UTR fragment with point mutations in the miRNA binding sites. These results suggest that targeting NFI-A in MDSCs during sepsis may enhance resistance to uncontrolled infection.
Bah, Isatou; Alkhateeb, Tuqa; Kumbhare, Ajinkya; Youssef, Dima; Yao, Zhi Q.; Hawkin, Gregory A.; McCall, Charles E.; and El Gazzar, Mohamed. 2020. HuR Promotes miRNA-Mediated Upregulation of NFI-A Protein Expression in MDSCs During Murine Sepsis. Molecular Immunology. Vol.123 97-105. https://doi.org/10.1016/j.molimm.2020.04.014 PMID: 32474254 ISSN: 0161-5890