Metabolic gatekeepers to safeguard against autoimmunity and oncogenic B cell transformation
Metabolic gatekeepers to safeguard against autoimmunity and oncogenic B cell transformation
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DOI：
10.1038/s41577-019-0154-3
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发表时间：
2019-05-01
影响因子：
100.3
通讯作者：
Muschen, Markus
中科院分区：
文献类型：
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作者：
Muschen, Markus
B细胞在葡萄糖和能量代谢方面面临多重限制。它们的谱系决定转录因子抑制葡萄糖摄取和磷酸戊糖途径的活性，而它们的线粒体数量少和细胞质体积小，为线粒体ATP的产生和自噬作为替代能源设置了狭窄的限制。在激活过程中，B细胞可以平衡能量消耗的暂时性增加。然而，永久性的过度激活，例如，自身反应性B细胞受体(BCR)下游或转化癌基因的下游，可能会导致能量应激和细胞死亡。在这里，我认为B细胞对三磷酸腺苷的内在限制是消除自身反应或癌前B细胞的一种保障。如果代谢门卫受到损害，额外葡萄糖的涌入可能会在自身反应性bcr或转化癌基因的驱动下，推动代谢需求的永久性增加和病理性B细胞增殖。
B cells face multiple restrictions on glucose and energy metabolism. Their lineage-determining transcription factors repress glucose uptake and pentose phosphate pathway activity, while their low numbers of mitochondria and small cytoplasmic volume set narrow limits for mitochondrial ATP production and autophagy as alternative energy sources. During activation, B cells can balance temporary increases of energy expenditure. However, permanent hyperactivation of kinases, for instance, downstream of an autoreactive B cell receptor (BCR) or a transforming oncogene, can cause energy stress and cell death. Here, I propose that B cell-intrinsic restriction of ATP represents a safeguard to eliminate autoreactive or pre-malignant B cells. If the metabolic gatekeepers are compromised, influx of additional glucose may fuel permanent increases in metabolic demands and pathological B cell proliferation, driven by an autoreactive BCR or a transforming oncogene.