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  3. Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity

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

  • Immunity. 2023 Oct 8:S1074-7613(23)00417-X. doi: 10.1016/j.immuni.2023.09.012.
Chunyuan Zhao 1,  Yunjin Ma 2,  Minghui Zhang 2,  Xiaoyan Gao 2,  Wenbo Liang 2,  Ying Qin 2,  Yue Fu 2,  Mutian Jia 2,  Hui Song 2,  Chengjiang Gao 3,  Wei Zhao 4
Affiliations

Affiliations

  • 1 Department of Pathogenic Biology, Key Laboratory of Infection and Immunity of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Cell Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 2 Department of Pathogenic Biology, Key Laboratory of Infection and Immunity of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 3 Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 4 Department of Pathogenic Biology, Key Laboratory of Infection and Immunity of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. Electronic address: [email protected].
PMID: 37848037 DOI: 10.1016/j.immuni.2023.09.012
Abstract

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

Keywords

B-DNA; Z-DNA; cGAS; innate immunity; polyamine metabolism; spermidine; spermine; type I IFNs.

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