PDF(Pubmed)
Abstract：
Bcl-3 is an atypical IκB family member that regulates transcription in the nucleus by binding to the p50/p52 homologous dimer subunit. Although various studies illustrate the important role of Bcl-3 in physiological function, its role in metabolism is still unclear. We found that Bcl-3 has a metabolic regulatory effect on autoimmunity. Bcl-3-depleted mice are unable to develop experimental autoimmune encephalomyelitis. The disease resistance was linked to an increase in lactate levels in Th17 cells, and lactate could alleviate EAE development in WT mice. Bcl-3 deficient mice had more differentiated Th17 cells and an increased extracellular acidification rate in these cells. Concurrently, their ultimate respiration rate and respiratory reserve capacity were significantly lower than wild-type mice. However, adding GNE-140 (LADH inhibitor) to Bcl-3-deficient Th17 cells could reverse the phenomenon, and lactate supplementation could increase the glycolysis metabolism of Th17 cells in WT mice. Mechanically, Bcl-3 could interact with Raptor through ANK and RNC domains. Therefore, Bcl-3 regulates Th17 pathogenicity by promoting Raptor mediated energy metabolism, revealing a novel regulation of adaptive immunity.
摘要：
Bcl-3是非典型IκB家族成员,其通过与p50/p52同源二聚体亚基结合来调节细胞核中的转录。尽管各种研究表明Bcl-3在生理功能中的重要作用，其在新陈代谢中的作用尚不清楚。我们发现Bcl-3对自身免疫具有代谢调节作用。Bcl-3耗尽的小鼠不能发展实验性自身免疫性脑脊髓炎。抗病性与Th17细胞中乳酸水平的增加有关，乳酸可以减轻WT小鼠的EAE发展。Bcl-3缺陷小鼠具有更多分化的Th17细胞和这些细胞中增加的细胞外酸化率。同时,它们的最终呼吸速率和呼吸储备能力明显低于野生型小鼠。然而,向Bcl-3缺陷的Th17细胞中加入GNE-140（LADH抑制剂）可以逆转这种现象，补充乳酸可以增加WT小鼠Th17细胞的糖酵解代谢。机械上,Bcl-3可以通过ANK和RNC域与Raptor相互作用。因此,Bcl-3通过促进Raptor介导的能量代谢调节Th17致病性,揭示了适应性免疫的新调控。
