STAT1/3 signaling suppresses axon degeneration and neuronal cell death through regulation of NAD+-biosynthetic and consuming enzymes
STAT1/3 signaling suppresses axon degeneration and neuronal cell death through regulation of NAD+-biosynthetic and consuming enzymes
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DOI：
10.1016/j.cellsig.2023.110717
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发表时间：
2023-05-17
影响因子：
4.8
通讯作者：
Sakaguchi，Masakiyo
中科院分区：
文献类型：
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作者：
Murata，Hitoshi;Yasui，Yu;Sakaguchi，Masakiyo
烟酰胺腺嘌呤二核苷酸（NAD+）生物合成和消耗酶通过调节NAD+代谢参与各种细胞内事件。最近，它已经变得清晰，在表达的NAD+-生物合成和消耗酶的变化有助于轴突的稳定性的神经元。我们探索了改变NAD+代谢酶表达的可溶性生物活性因子，发现细胞因子干扰素（IFN）-γ增加了烟酰胺核苷酸腺苷酰转移酶2（NMNAT 2）（一种NAD+生物合成酶）的表达。IFN-γ激活信号转导和转录激活因子1和3（STAT 1/3），随后抑制c-Jun N-末端激酶（JNK）。因此，STAT 1/3以剂量和时间依赖性方式在mRNA和蛋白质水平上增加NMNAT 2的表达，同时抑制无菌α和Toll/白细胞介素受体基序1（SARM 1）（一种NAD+消耗酶）的激活，并增加细胞内NAD+水平。我们研究了STAT 1/3信号对长春新碱介导的细胞损伤的保护作用，作为化疗诱导的周围神经病变（CIPN）的模型，其中轴突变性参与疾病进展。我们发现IFN-γ介导的STAT 1/3激活抑制长春新碱诱导的NMNAT 2下调和SARM 1磷酸化上调，导致随后的神经突降解和细胞死亡的适度抑制。这些结果表明，STAT 1/3信号转导诱导NMNAT 2表达，同时抑制SARM 1磷酸化，这两种作用有助于抑制轴突变性和细胞死亡。
Nicotinamide adenine dinucleotide (NAD)+-biosynthetic and consuming enzymes are involved in various intracellular events through the regulation of NAD+metabolism. Recently, it has become clear that alterations in the expression of NAD+-biosynthetic and consuming enzymes contribute to the axonal stability of neurons. We explored soluble bioactive factor(s) that alter the expression of NAD+-metabolizing enzymes and found that cytokine interferon (IFN)-γ increased the expression of nicotinamide nucleotide adenylyltransferase 2 (NMNAT2), an NAD+-biosynthetic enzyme. IFN-γ activated signal transducers and activators of transcription 1 and 3 (STAT1/3) followed by c-Jun N-terminal kinase (JNK) suppression. As a result, STAT1/3 increased the expression of NMNAT2 at both mRNA and protein levels in a dose- and time-dependent manner and, at the same time, suppressed activation of sterile alpha and Toll/interleukin receptor motif-containing 1 (SARM1), an NAD+-consuming enzyme, and increased intracellular NAD+levels. We examined the protective effect of STAT1/3 signaling against vincristine-mediated cell injury as a model of chemotherapy-induced peripheral neuropathy (CIPN), in which axonal degeneration is involved in disease progression. We found that IFN-γ-mediated STAT1/3 activation inhibited vincristine-induced downregulation of NMNAT2 and upregulation of SARM1 phosphorylation, resulting in modest suppression of subsequent neurite degradation and cell death. These results indicate that STAT1/3 signaling induces NMNAT2 expression while simultaneously suppressing SARM1 phosphorylation, and that both these actions contribute to suppression of axonal degeneration and cell death.