DDX41 is required for cGAS-STING activation against DNA virus infection

• Published in: Cell reports (Cambridge) 2022-05, Vol.39 (8), p.110856-110856, Article 110856
• Main Authors: Singh, Ravi Shankar, Vidhyasagar, Venkatasubramanian, Yang, Shizhuo, Arna, Ananna Bhadra, Yadav, Manisha, Aggarwal, Aanchal, Aguilera, Alexya N., Shinriki, Satoru, Bhanumathy, Kalpana Kalyanasundaram, Pandey, Kannupriya, Xu, Aizhang, Rapin, Noreen, Bosch, Mark, DeCoteau, John, Xiang, Jim, Vizeacoumar, Franco J., Zhou, Yan, Misra, Vikram, Matsui, Hirotaka, Ross, Susan R., Wu, Yuliang
• Format: Article
• Language: English
• Subjects: acute myeloid leukemia; Adenosine Triphosphate; AML; annealing; cGAS; DDX41; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; DNA - metabolism; DNA virus; DNA Virus Infections; Humans; Interferon Type I - metabolism; Leukemia, Myeloid, Acute; MDS; Membrane Proteins - genetics; Membrane Proteins - metabolism; myelodysplastic syndromes; Nucleotidyltransferases - metabolism; Signal Transduction; STING; unwinding
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110856

Upon binding double-stranded DNA (dsDNA), cyclic GMP-AMP synthase (cGAS) is activated and initiates the cGAS-stimulator of IFN genes (STING)-type I interferon pathway. DEAD-box helicase 41 (DDX41) is a DEAD-box helicase, and mutations in DDX41 cause myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). Here, we show that DDX41-knockout (KO) cells have reduced type I interferon production after DNA virus infection. Unexpectedly, activations of cGAS and STING are affected in DDX41 KO cells, suggesting that DDX41 functions upstream of cGAS. The recombinant DDX41 protein exhibits ATP-dependent DNA-unwinding activity and ATP-independent strand-annealing activity. The MDS/AML-derived mutant R525H has reduced unwinding activity but retains normal strand-annealing activity and stimulates greater cGAS dinucleotide-synthesis activity than wild-type DDX41. Overexpression of R525H in either DDX41-deficient or -proficient cells results in higher type I interferon production. Our results have led to the hypothesis that DDX41 utilizes its unwinding and annealing activities to regulate the homeostasis of dsDNA and single-stranded DNA (ssDNA), which, in turn, regulates cGAS-STING activation. [Display omitted] •DDX41 is required for cGAS-STING activation•DDX41 modulates the homeostasis of dsDNA through its unwinding and annealing activities•Patient mutant R525H has reduced unwinding activity but retains annealing activity•R525H causes excessive activation of innate immune response that might lead to MDS/AML cGAS is activated by dsDNA. Singh et al. find DDX41 regulates cGAS activation through unwinding and annealing activities on dsDNA and ssDNA, respectively, and MDS/AML patient mutant R525H causes overactivation of innate immune response due to its unbalanced activities. This DDX41-cGAS-STING pathway may be related to molecular pathogenesis of MDS/AML.