山东大学赵伟课题组探明了多胺代谢控制B到Z型DNA的过渡，以协调DNA传感器环鸟苷单磷酸(GMP)-AMP (cGAMP)合成酶(cGAS)活性。相关论文发表在2023年10月16日出版的《免疫》杂志上。

他们发现内源性多胺精胺和亚精胺减弱cGAS活性和先天免疫反应。机制上，精胺和亚精胺诱导B型DNA向Z型DNA (Z-DNA)转变，从而降低其与cGAS的结合亲和力。亚精胺/精胺N1 -乙酰转移酶1 (SAT1)是多胺分解代谢的限速酶，可降低细胞中精胺和亚精胺的浓度，通过抑制细胞中Z-DNA的积累而增强cGAS的激活。在体内，单纯疱疹病毒1 (HSV-1)缺乏可促进其复制。

结果表明，精胺和亚精胺诱导双链DNA (dsDNA)呈Z型构象，SAT1介导的多胺代谢协调cGAS活性。

研究人员表示，cGAS是一种通用的dsDNA传感器，可识别细胞质中的外源和自身DNA并启动先天免疫反应，并与各种感染和非感染情况有关。cGAS结合到dsDNA的主干并产生第二个信使cGAMP, cGAMP激活干扰素基因刺激因子(STING)。

附：英文原文

Title: Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity

Author: Chunyuan Zhao, Yunjin Ma, Minghui Zhang, Xiaoyan Gao, Wenbo Liang, Ying Qin, Yue Fu, Mutian Jia, Hui Song, Chengjiang Gao, Wei Zhao

Issue&Volume: 2023-10-16

Abstract: Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) synthase (cGAS) is a universal double-strandedDNA (dsDNA) sensor that recognizes foreign and self-DNA in the cytoplasm and initiatesinnate immune responses and has been implicated in various infectious and non-infectiouscontexts. cGAS binds to the backbone of dsDNA and generates the second messenger,cGAMP, which activates the stimulator of interferon genes (STING). Here, we show thatthe endogenous polyamines spermine and spermidine attenuated cGAS activity and innateimmune responses. Mechanistically, spermine and spermidine induced the transitionof B-form DNA to Z-form DNA (Z-DNA), thereby decreasing its binding affinity withcGAS. Spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzymein polyamine catabolism that decreases the cellular concentrations of spermine andspermidine, enhanced cGAS activation by inhibiting cellular Z-DNA accumulation; SAT1deficiency promoted herpes simplex virus 1 (HSV-1) replication in vivo. The results indicate that spermine and spermidine induce dsDNA to adopt the Z-formconformation and that SAT1-mediated polyamine metabolism orchestrates cGAS activity.

DOI: 10.1016/j.immuni.2023.09.012

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00417-X