Research Article: HuR ablation destabilizes Foxp3 mRNA and impairs regulatory T cell function, contributing to an autoimmune phenotype
Abstract:
The RNA-binding protein HuR (Elavl1), a key post-transcriptional regulator, plays a critical role in T cell activation and function by stabilizing target mRNAs. To investigate the role of HuR in regulatory T cell (Treg) function, we generated the Foxp3YFP/Cre HuRfl/fl mouse model.
In this model, homozygous females and hemizygous males for Foxp3 developed a scurfy-like phenotype displaying autoimmune features, including failure to thrive, splenomegaly, hair loss, tail stippling, and widespread multi-organ immune cell infiltration. Molecular analysis included direct interaction studies between HuR and Foxp3 mRNA to assess mRNA stability, RNA sequencing of YFP? Tregs, Protein-Protein Interaction (PPI) analysis, qPCR, and Treg functional assays.
To our knowledge, this is the first study demonstrating that HuR directly binds and stabilizes Foxp3 mRNA in Tregs, using a novel Treg-specific HuR-deficient mouse model, with implications for autoimmune regulation. Foxp3 mRNA stability and expression were significantly reduced in Tregs from these HuR KO mice, despite higher frequencies of YFP? Tregs. RNA sequencing revealed significant dysregulation of several pathways, including the T helper differentiation pathway, in which Foxp3 played a central role. PPI analysis showed a direct link between Foxp3 and Rorc (encoding ROR?t), connecting Foxp3 to the T cell differentiation pathway via IL-23R. Our qPCR analysis supported these findings. Functional assays demonstrated a reduction in the suppressive capacity of HuR-deficient Tregs.
These findings together suggest that ablation of HuR in Tregs disrupts Foxp3 expression and Treg function, likely through dysregulation of T cell differentiation pathways involving ROR?t. This potentially contributes to a disrupted Treg–Th17 axis and autoimmune dysfunction. These data suggest that HuR-mediated post-transcriptional regulation contributes to maintaining Foxp3 expression and immune homeostasis, although compensatory mechanisms such as increased IL-10 expression may also be involved.
Introduction:
The RNA-binding protein HuR (Elavl1), a key post-transcriptional regulator, plays a critical role in T cell activation and function by stabilizing target mRNAs. To investigate the role of HuR in regulatory T cell (Treg) function, we generated the Foxp3YFP/Cre HuRfl/fl mouse model.
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