HuR Plays a Positive Role to Strengthen the Signaling Pathways of CD4+ T Cell Activation and Th17 Cell Differentiation

Abstract

After antigen and/or different cytokine stimulation, CD4+ T cells activated and differentiated into distinct T helper (Th) cells via differential T cell signaling pathways. Transcriptional regulation of the activation and differentiation of naïve CD4+ T cells into distinct lineage Th cells such as Th17 cells has been fully studied. However, the role of RNA-binding protein HuR in the signaling pathways of their activation and differentiation has not been well characterized. Here, we used HuR conditional knockout (HuR KO) CD4+ T cells to study mechanisms underlying HuR regulation of T cell activation and differentiation through distinct signaling pathways. Our work showed that, mechanistically, HuR positively promoted CD3g expression by binding its mRNA and enhanced the expression of downstream adaptor Zap70 and Malt1 in activated CD4+ T cells. Compared to WT Th0 cells, HuR KO Th0 cells with reduced Bcl-2 expression are much more susceptible to apoptosis than WT Th0 cells. We also found that HuR stabilized IL-6Rα mRNA and promoted IL-6Rα protein expression, thereby upregulating its downstream phosphorylation of Jak1 and Stat3 and increased level of phosphorylation of IκBα to facilitate Th17 cell differentiation. However, knockout of HuR increased IL-22 production in Th17 cells, which was due to HuR deficiency in reducing IL-22 transcription repressor c-Maf expression. These results highlight the importance of HuR in TCR signaling and IL-6/IL-6R axis driving naïve CD4+ T cell activation and differentiation into Th17 cells.

CRISPR/Cas9-Mediated Knockout of the HuR Gene in U251 Cell Inhibits Japanese Encephalitis Virus Replication

“…Chellappan et al employed SRI-42127 to inhibit the nuclear shuttling function of HuR, thus suppressing its protein activity [ 40 ]. Additionally, some studies obtained HuR gene knockout cells from mice with conditional HuR gene deletion for subsequent experiments [ 41 , 42 ]. We leveraged the CRISPR/Cas9 gene-editing system to entirely and permanently ablate endogenous HuR expression.…”

RNY3 modulates cell proliferation and IL13 mRNA levels in a T lymphocyte model: a possible new epigenetic mechanism of IL-13 regulation

“…First, hY3 is part of ribonucleoprotein complexes and binds to proteins involved in mRNA processing and splicing, such as HuR (ELAVL1) [ 16 ]. Interestingly, HuR is involved in T cell activation response and differentiation [ 13 , 31 ]. Also, Karginov et al showed that HuR produced a broad control through upstream factors during T cell activation and that its depletion produced NFAT1 upregulation and NFAT2 downregulation [ 13 ].…”

Aberrant blood MALT1 and its relevance with multiple organic dysfunctions, T helper cells, inflammation, and mortality risk of sepsis patients

“…Beyond that, MALT1 overexpression could result in kidney injury via activating nuclear factor κB (NF‐κB) signaling 15 . Additionally, it is illustrated that MALT1 enhances the differentiation of CD4 + T cells into Th1 and Th17 cells, meanwhile the differentiation of CD4 + T cells into Th1 and Th17, which are important in the pathology of sepsis 18–21 . However, the clinical relevance of MALT1 with sepsis, which is one of the most serious infection‐related diseases, still remains elusive.…”