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Innate Immunity: Mechanisms and Modulation | EK39


EK39-eposter-wu-yuliang - DDX41 Helicase Modulates cGAS-STING Activation Through Its Unwinding and Annealing Activities


Apr 12, 2021 12:00am ‐ Apr 12, 2021 12:00am

Description

DDX41 Helicase Modulates cGAS-STING Activation Through Its Unwinding and Annealing Activities Ravi Shankar Singh1, Venkatasubramanian Vidhyasagar1, Shizhuo Yang1, Manisha Yadav1, Aanchal Aggarwal1, Ananna Bhadra Arna1, Alexya N. Aguilera2, Satoru Shinriki3, Kalpana Kalyanasundaram Bhanumathy4, Kannupriya Pandey5, Aizhang Xu4, Noreen Rapin6, Mark Bosch4, John DeCoteau7, Jim Xiang4, Franco J. Vizeacoumar4,7, Yan Zhou5,6, Vikram Misra6, Hirotaka Matsui3, Susan R. Ross2, and Yuliang Wu1,* 1Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada 2Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA 3Department of Molecular Laboratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan 4Saskatchewan Cancer Agency, Saskatoon, SK S7N 5E5, Canada 5Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada 6Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada 7Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada Abstract Upon binding double-stranded (ds)DNA, cGAS is activated and initiates the cGAS-STING-type I interferon pathway; thus, the availability of dsDNA ligand is critical for cGAS activation. DDX41 is a DEAD-box helicase and mutations in DDX41 cause myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, we found that DDX41-knockout (KO) human cells and mice primary cells had reduced type I interferon production after viral infection, which is consistent with previous reports. Unexpectedly, cGAS and STING activation were affected in DDX41 KO cells, suggesting that DDX41 functions upstream of cGAS. The recombinant DDX41 protein exhibited ATP-dependent DNA unwinding activity and ATP-independent strand annealing activity. The MDS/AML-derived mutant R525H had reduced unwinding activities but retained normal strand annealing activity and stimulated greater cGAS dinucleotide synthesis activity than WT-DDX41. Overexpression of R525H in either DDX41-deficient or -proficient cells resulted in higher type I interferon production, indicating that DDX41 inactivates cGAS-STING-type I interferon pathway by unwinding dsDNA to single-stranded (ss)DNA. Our results demonstrate that DDX41 utilizes its unwinding and annealing activities to regulate the homeostasis of dsDNA and ssDNA, which in turn modulates the cGAS-STING pathway; dysregulation of this pathway leads to MDS/AML.

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