HuR promotes miRNA-mediated upregulation of NFI-A protein expression in MDSCs during murine sepsis
- Resource Type
- Authors
- Dima Youssef; Gregory A. Hawkin; Isatou Bah; Mohamed El Gazzar; Charles E. McCall; Ajinkya Kumbhare; Zhi Q. Yao; Tuqa Alkhateeb
- Source
- Mol Immunol
- Subject
- 0301 basic medicine
Untranslated region
Male
Transcriptional Activation
Immunology
MiRNA binding
Article
ELAV-Like Protein 1
03 medical and health sciences
Mice
0302 clinical medicine
Downregulation and upregulation
Sepsis
microRNA
Protein biosynthesis
Animals
Molecular Biology
Transcription factor
Cells, Cultured
Messenger RNA
Mice, Inbred BALB C
Chemistry
Myeloid-Derived Suppressor Cells
MRNA stabilization
Up-Regulation
MicroRNAs
NFI Transcription Factors
030104 developmental biology
Cancer research
030215 immunology
- Language
- English
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.