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首页> 外文期刊>Molecular and Cellular Biology >Conditional Knockout Mice Reveal an Essential Role of Protein Phosphatase 4 in Thymocyte Development and Pre-T-Cell Receptor Signaling
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Conditional Knockout Mice Reveal an Essential Role of Protein Phosphatase 4 in Thymocyte Development and Pre-T-Cell Receptor Signaling

机译：有条件的基因敲除小鼠揭示蛋白质磷酸酶4在胸腺细胞发育和前T细胞受体信号传导中的重要作用。

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Okadaic acid-sensitive serine/threonine phosphatases have been shown to regulate interleukin-2 transcription and T-cell activation. Okadaic acid inhibits protein phosphatase 4 (PP4), a novel PP2A-related serine/threonine phosphatase, at a 50% inhibitory concentration (IC50) comparable to that for PP2A. This raises the possibility that some cellular functions of PP2A, determined in T cells by using okadaic acid, may in fact be those of PP4. To investigate the in vivo roles of PP4 in T cells, we generated conventional and T-cell-specific PP4 conditional knockout mice. We found that the ablation of PP4 led to the embryonic lethality of mice. PP4 gene deletion in the T-cell lineage resulted in aberrant thymocyte development, including T-cell arrest at the double-negative 3 stage (CD4? CD8? CD25+ CD44?), abnormal thymocyte maturation, and lower efficacy of positive selection. PP4-deficient thymocytes showed decreased proliferation and enhanced apoptosis in vivo. Analysis of pre-T-cell receptor (pre-TCR) signaling further revealed impaired calcium flux and phospholipase C-γ1-extracellular signal-regulated kinase activation in the absence of PP4. Anti-CD3 injection in PP4-deficient mice led to enhanced thymocyte apoptosis, accompanied by increased proapoptotic Bim but decreased antiapoptotic Bcl-xL protein levels. In the periphery, antigen-specific T-cell proliferation and T-cell-mediated immune responses in PP4-deficient mice were dramatically compromised. Thus, our results indicate that PP4 is essential for thymocyte development and pre-TCR signaling.
机译：冈田酸敏感的丝氨酸/苏氨酸磷酸酶已被证明可调节白介素2转录和T细胞活化。冈田酸以与PP2A相当的50％抑制浓度（IC 50 ）抑制PP2A相关的一种新型丝氨酸/苏氨酸磷酸酶蛋白磷酸酶4（PP4）。这增加了使用冈田酸在T细胞中确定的PP2A的某些细胞功能实际上可能是PP4的功能。为了研究PP4在T细胞中的体内作用，我们生成了常规的和T细胞特异性的PP4条件性基因敲除小鼠。我们发现消融PP4导致小鼠的胚胎致死率。 T细胞谱系中的PP4基因缺失导致胸腺细胞异常发育，包括T细胞在双阴性3期停滞（CD4 ？ CD8 ？ CD25 + CD44 ？），胸腺细胞异常成熟和阳性选择功效较低。 PP4缺乏的胸腺细胞在体内显示出减少的增殖和增强的细胞凋亡。对前T细胞受体（pre-TCR）信号的分析进一步揭示了在不存在PP4的情况下钙通量受损和磷脂酶C-γ1-细胞外信号调节的激酶激活。在PP4缺陷型小鼠中抗CD3注射导致胸腺细胞凋亡增强，并伴随着促凋亡Bim增加，但抗凋亡Bcl-xL蛋白水平降低。在外围，PP4缺陷小鼠的抗原特异性T细胞增殖和T细胞介导的免疫反应受到严重损害。因此，我们的结果表明PP4对于胸腺细胞发育和pre-TCR信号传导至关重要。

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