Abstract：
NAD+ metabolism is involved in many biological processes. However, the underlying mechanism of how NAD+ metabolism is regulated remains elusive. Here, we find that PTIP governs NAD+ metabolism in macrophages by regulating CD38 expression and is required for macrophage inflammation. Through integrating histone modifications with NAD+ metabolic gene expression profiling, we identify PTIP as a key factor in regulating CD38 expression, the primary NAD+-consuming enzyme in macrophages. Interestingly, we find that PTIP deletion impairs the proinflammatory response of primary murine and human macrophages, promotes their metabolic switch from glycolysis to oxidative phosphorylation, and alters NAD+ metabolism via downregulating CD38 expression. Mechanistically, an intronic enhancer of CD38 is identified. PTIP regulates CD38 expression by cooperating with acetyltransferase p300 in establishing the CD38 active enhancer with enriched H3K27ac. Overall, our findings reveal a critical role for PTIP in fine-tuning the inflammatory responses of macrophages via regulating NAD+ metabolism.
摘要：
NAD+代谢涉及许多生物过程。然而,NAD+代谢如何调节的潜在机制仍然难以捉摸。这里,我们发现PTIP通过调节CD38表达来控制巨噬细胞中的NAD+代谢,并且是巨噬细胞炎症所必需的.通过整合组蛋白修饰与NAD+代谢基因表达谱，我们确定PTIP是调节CD38表达的关键因素，巨噬细胞中主要的NAD+消耗酶。有趣的是,我们发现PTIP缺失会损害原代鼠和人巨噬细胞的促炎反应，促进他们从糖酵解到氧化磷酸化的代谢转换，并通过下调CD38表达改变NAD+代谢。机械上,鉴定了CD38的内含子增强子。PTIP通过与乙酰转移酶p300合作建立富含H3K27ac的CD38活性增强子来调节CD38的表达。总的来说,我们的发现揭示了PTIP通过调节NAD+代谢在微调巨噬细胞炎症反应中的关键作用.
