Identification of PGAM5 as a Mammalian Protein Histidine Phosphatase that Plays a Central Role to Negatively Regulate CD4(+) T Cells.
Identification of PGAM5 as a Mammalian Protein Histidine Phosphatase that Plays a Central Role to Negatively Regulate CD4(+) T Cells.
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DOI：
10.1016/j.molcel.2016.06.021
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发表时间：
2016-08-04
期刊：
影响因子：
16
通讯作者：
Skolnik EY
中科院分区：
文献类型：
--
作者：
Panda S;Srivastava S;Li Z;Vaeth M;Fuhs SR;Hunter T;Skolnik EY
虽然丝氨酸、苏氨酸和酪氨酸的磷酸化已经被很好地表征，但组氨酸磷酸化在哺乳动物信号传导中的作用在很大程度上尚未被探索。在这里，我们发现磷酸甘油酸突变酶家族5 （PGAM5）作为一种磷酸组氨酸磷酸酶起作用，它特异性地结合核苷二磷酸激酶B （NDPK-B）上的催化组氨酸并使其去磷酸化。通过去磷酸化NDPK-B， PGAM5通过抑制NDPK-B介导的组氨酸磷酸化和K+通道KCa3.1的激活来负性调节CD4+ T细胞，这是TCR刺激的Ca2+内流和细胞因子产生所必需的。利用最近开发的特异性识别咪唑环N1 （1-pHis）或N3 （3-pHis）位置氮磷酸化的单克隆抗体，我们首次在体内检测到组氨酸磷酸化蛋白的磷异构体特异性调控，并将这些修饰与TCR信号联系起来。这些结果在研究组氨酸磷酸化在哺乳动物生物学和疾病中的作用方面迈出了重要的一步。哺乳动物中蛋白质组氨酸磷酸化的定义不明确。Panda等人发现磷酸甘油酸突变酶5 （PGAM5）是一种哺乳动物组氨酸磷酸酶，它特异性地使H118上的NDPK-B去磷酸化，从而抑制3-pHis的磷酸化和K+通道KCa3.1的激活。PGAM5通过抑制KCa3.1通道激活，负调控TCR刺激的CD4+ T细胞中Ca2+内流和促炎细胞因子的产生。
Whereas phosphorylation of serine, threonine, and tyrosine is exceedingly well characterized, the role of histidine phosphorylation in mammalian signaling is largely unexplored. Here we show that phosphoglycerate mutase family 5 (PGAM5) functions as a phosphohistidine phosphatase that specifically associates with and dephosphorylates the catalytic histidine on Nucleoside Diphosphate Kinase B (NDPK-B). By dephosphorylating NDPK-B, PGAM5 negatively regulates CD4+ T cells by inhibiting NDPK-B mediated histidine phosphorylation and activation of the K+ channel KCa3.1, which is required for TCR stimulated Ca2+ influx and cytokine production. Using recently developed monoclonal antibodies that specifically recognize phosphorylation of nitrogens at the N1 (1-pHis) or N3 (3-pHis) positions of the imidazole ring, we detect for the first time phosphoisoform specific regulation of histidine phosphorylated proteins in vivo, and link these modifications to TCR signaling. These results represent an important step forward in studying the role of histidine phosphorylation in mammalian biology and disease. Protein histidine phosphorylation in mammals has been poorly defined. Panda et al. identify phosphoglycerate mutase 5 (PGAM5) as a mammalian histidine phosphatase that specifically dephosphorylates NDPK-B on H118 thereby inhibiting 3-pHis phosphorylation and activation of the K+ channel KCa3.1. By inhibiting KCa3.1 channel activation, PGAM5 functions to negatively regulate TCR stimulated Ca2+ influx and pro-inflammatory cytokine production in CD4+ T cells.
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影响因子：
5.6
作者：
Sadatomi D;Tanimura S;Ozaki K;Takeda K
通讯作者：
Takeda K
影响因子：
3.9
作者：
Attwood, Paul V.
通讯作者：
Attwood, Paul V.
DOI：
10.1016/s0006-291x(03)00920-3
发表时间：
2003-06-20
影响因子：
3.1
作者：
Klumpp, S;Bechmann, G;Krieglstein, J
通讯作者：
Krieglstein, J
DOI：
10.1073/pnas.90.24.11713
发表时间：
1993-12-15
影响因子：
11.1
作者：
LEE, CH;LI, W;SKOLNIK, EY
通讯作者：
SKOLNIK, EY
影响因子：
3.3
作者：
Srivastava, Shekhar;Di, Lie;Skolnik, Edward Y.
通讯作者：
Skolnik, Edward Y.