The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration.
The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration.
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DOI：
10.1016/j.jbc.2021.100905
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Masters SL
中科院分区：
文献类型：
--
作者：
Jackson JT;Mulazzani E;Nutt SL;Masters SL
磷脂酰肌醇特异性磷脂酶Cγ2(PLCγ2)是一种重要的信号分子，由多种细胞表面受体下游激活，这些受体含有细胞内基于酪氨酸的免疫受体激活基序。这些受体招募诸如Syk、Btk和BLNK等激酶来磷酸化和激活PLCγ2，然后产生1D-肌醇1，4，5-三磷酸和二酰甘油。这些众所周知的第二信使是多种细胞膜功能所必需的，包括细胞增殖、内吞作用和钙离子通量。因此，PLCγ2功能障碍与多种疾病有关，包括癌症、神经退行性变和免疫紊乱。与PLCγ2相关的各种病理以不同的遗传变异为例。该基因座的遗传突变会导致PLCγ2相关抗体缺陷和免疫失调，在某些情况下还会出现自体炎症。该基因的获得性突变通常是由于抑制BTK治疗慢性淋巴细胞白血病而引起的，导致结构性下游信号转导和淋巴细胞增殖。最后，第三组PLCγ2变体实际上对各种神经退行性疾病具有保护作用，推测是通过增加对有害神经集合体的摄取和降解。因此，上调或下调PLCγ2活性可能具有治疗作用；然而，在实现这种临床实用之前，我们需要更好地了解这些变体所传播的信号通路。在这里，我们回顾了PLCγ2在造血细胞中的信号作用，以帮助了解突变导致免疫紊乱和癌症的影响，并由此推断可能与保护神经退行性变有关的作用。
Phosphatidylinositol-specific phospholipase Cγ2 (PLCγ2) is a critical signaling molecule activated downstream from a variety of cell surface receptors that contain an intracellular immunoreceptor tyrosine-based activation motif. These receptors recruit kinases such as Syk, BTK, and BLNK to phosphorylate and activate PLCγ2, which then generates 1D-myo-inositol 1,4,5-trisphosphate and diacylglycerol. These well-known second messengers are required for diverse membrane functionality including cellular proliferation, endocytosis, and calcium flux. As a result, PLCγ2 dysfunction is associated with a variety of diseases including cancer, neurodegeneration, and immune disorders. The diverse pathologies associated with PLCγ2 are exemplified by distinct genetic variants. Inherited mutations at this locus cause PLCγ2-associated antibody deficiency and immune dysregulation, in some cases with autoinflammation. Acquired mutations at this locus, which often arise as a result of BTK inhibition to treat chronic lymphocytic leukemia, result in constitutive downstream signaling and lymphocyte proliferation. Finally, a third group of PLCγ2 variants actually has a protective effect in a variety of neurodegenerative disorders, presumably by increased uptake and degradation of deleterious neurological aggregates. Therefore, manipulating PLCγ2 activity either up or down could have therapeutic benefit; however, we require a better understanding of the signaling pathways propagated by these variants before such clinical utility can be realized. Here, we review the signaling roles of PLCγ2 in hematopoietic cells to help understand the effect of mutations driving immune disorders and cancer and extrapolate from this to roles which may relate to protection against neurodegeneration.
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影响因子：
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作者：
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