AKT phosphorylation of hnRNPA1 modulates T cell fate and function

HnRNPA1和hnRNPL的AKT磷酸化调节T细胞的命运和功能 调节性T细胞(Treg)在维持自身耐受和预防 自身免疫性疾病。我们和其他人已经表明，低剂量有利于Treg和T辅助(Th)2细胞 分化，而高银剂量刺激激活PI3K/Akt/mTOR通路，有利于炎症 Th1和Th17细胞分化(Tef)。PI3K/Akt/mTOR信号通路的差异不仅影响T细胞的命运，而且 我们的研究表明，Akt磷酸化的RNA结合蛋白(RBP)是异质核 核糖核蛋白(HnRNP)A1，依赖于TCR信号强度。像hnRNPA1这样的限制性商业惯例正在出现 作为免疫细胞中RNA加工和稳定性的调节者，RBP对T细胞分化的影响是 一个日益令人感兴趣的话题。我们已经展示了hnRNPA1是最佳Treg分化所必需的，通过 进行击倒实验，并在低剂量刺激后被Akt磷酸化。我们的 目前的研究集中在确定Akt磷酸化在hnRNPA1功能中的作用。HnRNPA1是 已知在S199上有一个Akt磷酸化位点，我们的实验室已经产生了一个新的突变小鼠 型号：hnRNPA1-S199A(MA1)。这种突变影响Akt在ALL中磷酸化hnRNPA1的能力 免疫细胞。初步数据表明，低TCR刺激诱导的Treg分化在 突变小鼠身上的T细胞。根据这些初步发现，我们假设Akt介导的 低TCR刺激下hnRNPL和/或hnRNPA1的磷酸化控制着 参与Treg分化的RNA转录本。提出了以下具体目标：1)确定 HnRNPA1-S199A突变如何影响T细胞的命运和功能。2)确定hnRNPA1的影响 关于RNA剪接和稳定性。3)确定hnRNPL上AKT的磷酸化位点。4)确定如何 HnRNPL影响T细胞的命运和功能。

AKT phosphorylation of hnRNPA1 and hnRNPL modulates T cell fate and function Regulatory T cells (Treg) play a significant role in maintaining self-tolerance and preventing autoimmune diseases. We and others have shown that low dose favors Treg and T helper (Th) 2 cell differentiation, while high Ag dose stimulation activates the PI3K/Akt/mTOR pathway, favoring inflammatory Th1 and Th17 cell differentiation (Teff). Differences in PI3K/Akt/mTOR signaling not only affect T cell fate but our research shows that Akt phosphorylation of the RNA-binding protein, (RBP) heterogeneous nuclear ribonucleoprotein (hnRNP) A1, is dependent on TCR signal strength. RBPs such as hnRNPA1 are emerging as regulators of RNA processing and stability in immune cells, and the effect of RBP on T cell differentiation is a growing subject of interest. We have shown hnRNPA1 is required for optimal Treg differentiation by performing knockdown experiments, and that it is phosphorylated by Akt following low dose stimulation. Our present research is focused on identifying a role for Akt phosphorylation in hnRNPA1 function. HnRNPA1 is known to have a single Akt phosphorylation site at S199 and our lab has generated a new mutant mouse model, hnRNPA1-S199A (mA1). This mutation affects the ability of Akt to phosphorylate hnRNPA1 in all immune cells. Preliminary data suggest that Treg differentiation induced by low TCR stimulation is impaired in the T cells from the mutant mouse. Based on these preliminary findings we hypothesize that Akt-mediated phosphorylation of hnRNPL and/or hnRNPA1 upon low TCR stimulation controls the processing of RNA transcripts involved in Treg differentiation. The following specific aims are proposed; 1) To determine how the hnRNPA1-S199A mutation affects T cell fate and function. 2) To determine the impact hnRNPA1 has on RNA splicing and stability. 3) To identify the AKT phosphorylation site on hnRNPL. 4)To determine how hnRNPL effects T cell fate and function.