An alternative mode of CD43 signal transduction activates pro-survival pathways of T lymphocytes
An alternative mode of CD43 signal transduction activates pro-survival pathways of T lymphocytes
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DOI：
10.1111/imm.12670
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发表时间：
2017-01-01
期刊：
影响因子：
6.4
通讯作者：
Rosenstein, Yvonne
中科院分区：
文献类型：
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作者：
Elena Bravo-Adame, Maria;Vera-Estrella, Rosario;Rosenstein, Yvonne
CD 43是T细胞表面上最丰富的共刺激分子之一;它通过其胞质结构域转导活化信号，有助于调节T细胞应答的结果。本研究的目的是揭示这种唾液粘蛋白调控的新信号通路。蛋白质丰度的变化分析使我们能够确定丙酮酸激酶同工酶M2（PKM 2），糖酵解途径的酶，作为一个元素，可能参与信号级联产生的CD 43和T细胞受体（TCR）的参与。我们发现这种酶的糖酵解活性在TCR+ CD 43共刺激下没有显著增加，但PKM 2被酪氨酸磷酸化，表明它正在执行月光功能。我们报道了TCR+ CD 43共刺激诱导PKM 2的Y-105和信号转导和转录激活因子3的Y-705的磷酸化，导致丝裂原活化蛋白激酶激酶5/细胞外信号调节激酶5（MEK 5/ERK 5）通路的激活。ERK 5和cAMP反应元件结合蛋白（CREB）被激活，c-Myc和核因子jB（p65）核定位以及Bad磷酸化增强。与此一致，在鼠T细胞杂交瘤中表达人CD 43有利于细胞存活。总之，我们的数据突出了T淋巴细胞中CD 43分子的新信号传导途径，并强调了CD 43通过代谢酶的非糖酵解功能促进细胞存活的作用。
CD43 is one of the most abundant co-stimulatory molecules on a T-cell surface; it transduces activation signals through its cytoplasmic domain, contributing to modulation of the outcome of T-cell responses. The aim of this study was to uncover new signalling pathways regulated by this sialomucin. Analysis of changes in protein abundance allowed us to identify pyruvate kinase isozyme M2 (PKM2), an enzyme of the glycolytic pathway, as an element potentially participating in the signalling cascade resulting from the engagement of CD43 and the T-cell receptor (TCR). We found that the glycolytic activity of this enzyme was not significantly increased in response to TCR+ CD43 co-stimulation, but that PKM2 was tyrosine phosphorylated, suggesting that it was performing moonlight functions. We report that phosphorylation of both Y-105 of PKM2 and of Y-705 of signal transducer and activator of transcription 3 was induced in response to TCR+ CD43 co-stimulation, resulting in activation of the mitogen-activated protein kinase kinase 5/ extracellular signal-regulated kinase 5 (MEK5/ ERK5) pathway. ERK5 and the cAMP response element binding protein (CREB) were activated, and c-Myc and nuclear factor-jB (p65) nuclear localization, as well as Bad phosphorylation, were augmented. Consistent with this, expression of human CD43 in a murine T-cell hybridoma favoured cell survival. Altogether, our data highlight novel signalling pathways for the CD43 molecule in T lymphocytes, and underscore a role for CD43 in promoting cell survival through non-glycolytic functions of metabolic enzymes.