PTIP governs NAD+ metabolism by regulating CD38 expression to drive macrophage inflammation

Summary

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.