Mitochondrial p32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation
Mitochondrial p32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation
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DOI：
10.1016/j.celrep.2018.10.057
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发表时间：
2018-11-13
期刊：
影响因子：
8.8
通讯作者：
Kang, Dongchon
中科院分区：
文献类型：
--
作者：
Gotoh, Kazuhito;Morisaki, Takafumi;Kang, Dongchon
Toll 样受体激动剂诱导的树突状细胞 (DC) 成熟需要激活下游信号转导和代谢变化。内源性代谢物柠檬酸盐最近已成为 DC 激活的调节剂。然而，支持柠檬酸盐产生的代谢需求仍然不明确。在这里，我们证明 p32/C1qbp 作为线粒体中的多功能伴侣蛋白，支持线粒体代谢和 DC 成熟。代谢分析表明，在 p32 缺陷的 DC 中，脂多糖 (LPS) 诱导的柠檬酸增加受到损害。我们还发现 p32 与二氢硫辛酰胺 S-乙酰转移酶（丙酮酸脱氢酶 [PDH] 复合物的 E2 成分）相互作用，并正向调节 DC 中的 PDH 活性。因此，我们认为 DC 成熟是通过 p32 依赖性 PDH 活性通过柠檬酸产生来调节的。给予PDH抑制剂的p32缺失小鼠显示体内DC成熟和卵清蛋白特异性IgG产生减少，这表明p32可以作为DC相关自身免疫性疾病的治疗靶点。
Dendritic cell (DC) maturation induced by Toll-like receptor agonists requires activation of downstream signal transduction and metabolic changes. The endogenous metabolite citrate has recently emerged as a modulator of DC activation. However, the metabolic requirements that support citrate production remain poorly defined. Here, we demonstrate that p32/C1qbp, which functions as a multifunctional chaperone protein in mitochondria, supports mitochondrial metabolism and DC maturation. Metabolic analysis revealed that the citrate increase induced by lipopolysaccharide (LPS) is impaired in p32-deficient DCs. We also found that p32 interacts with dihy-drolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase [PDH] complex) and positively regulates PDH activity in DCs. Therefore, we suggest that DC maturation is regulated by citrate production via p32-dependent PDH activity. p32-null mice administered a PDH inhibitor show decreased DC maturation and ovalbumin-specific IgG production in vivo, suggesting that p32 may serve as a therapeutic target for DC-related autoimmune diseases.