Recently, Professor Zhao Wei's research team from the School of Basic Medical Sciences, Shandong University published a research paper entitled" Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity" in Immunity. Assistant research fellow Zhao Chunyuan and PhD student Ma Yunjin are the co-first authors. Professor Zhao Wei is the corresponding author.

The detection of microbial- or host-derived DNAs in the cytosol by cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a crucial role in the immunity of many organisms. Upon double-stranded DNA (dsDNA)engagement, cGAS catalyzes the conversion of GTP and ATP to cGAMP and activates the downstream signaling effect to initiate type I interferon (IFN) expression and inflammatory responses. Additionally,cGAS mediates the protective immune response against microbial infections and participates in various non-infectious contexts (e.g. inflammatory diseases, antitumor immunity, and cellular senescence). Therefore, precise regulation of cGAS activity is necessary to eliminate invading pathogens and prevent their detrimental effects.

cGAS recognizes adequate amounts of cytoplasmic DNA (cytoDNA) in a sequence-independent manner and triggers downstream signaling. cGAS binds to the B-form of dsDNA viaits positively charged surface and zinc thumb to interact with the DNA backbone. The other kind of DNA, Z-DNA has a left-handed configuration and its backbone has a zigzag arrangement.  The distinct conformation of Z-DNA implies that its cGAS affinity may differ from that of B-DNA. This study showed that two endogenous polyamines, spermine and spermidine, induce a B-to-Z DNA transition, thereby decreasing the binding affinity of dsDNAfor cGAS and thus attenuating host defense against herpes simplex virus 1(HSV-1; a type of DNA virus recognized by cGAS). Spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism that decreased the cellular concentrations of spermine and spermidine, enhanced cGAS activation by inhibiting cellular Z-DNA accumulation. The results of this study reveal an additional mechanism for preventing abnormal cytoDNA recognition and provide promising therapeutic targets for the treatment of diseases involving improper Z-DNA accumulation and aberrant cGAS activity.

Schematic representation of SAT1 controls B-to-Z DNA transition to orchestrate cGAS activity

This work was supported by grants from the National Natural Science Foundation of China, the Innovative Group Project of the Climbing Program of Shandong University, and Young Scholar's Future Plan Cultivation Project of Shandong University.

Link to the article: https://www.cell.com/immunity/fulltext/S1074-7613(23)00417-X