DDX41 is required for cGAS-STING activation against DNA virus infection. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • May 24, 2022

Research

keywords

  • DNA Virus Infections
  • Interferon Type I
  • Leukemia, Myeloid, Acute

Identity

PubMed Central ID

  • PMC9205463

Scopus Document Identifier

  • 85130589272

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2022.110856

PubMed ID

  • 35613581

Additional Document Info

volume

  • 39

issue

  • 8