The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, No.185, East Lake Road, Wuchang District, Wuhan, Hubei 430071, China.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, No.185, East Lake Road, Wuchang District, Wuhan, Hubei 430071, China.
Cell Rep. 2022 Mar 29;38(13):110603. doi: 10.1016/j.celrep.2022.110603.
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.
NAD 代谢参与许多生物过程。然而，NAD 代谢如何受到调节的潜在机制仍难以捉摸。在这里，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。通过将组蛋白修饰与 NAD 代谢基因表达谱进行整合，我们确定 PTIP 是调节 CD38 表达的关键因素，CD38 是巨噬细胞中主要的 NAD 消耗酶。有趣的是，我们发现 PTIP 缺失会损害原代小鼠和人类巨噬细胞的促炎反应，促进它们的代谢从糖酵解向氧化磷酸化转变，并通过下调 CD38 表达来改变 NAD 代谢。从机制上讲，我们鉴定到了 CD38 的一个内含子增强子。PTIP 通过与乙酰转移酶 p300 合作，在富含 H3K27ac 的 CD38 活性增强子上建立起作用，从而调节 CD38 的表达。总的来说，我们的研究结果揭示了 PTIP 通过调节 NAD 代谢精细调控巨噬细胞炎症反应的关键作用。
