Work

Deoxyribonuclease DNASE1L3 promotes innate immunity against DNA virus infection by enhancing the cGAS-STING pathway

Year: 2026

Type: article

Abstract: Deoxyribonucleases are known to scavenge self-DNA to dampen innate immune responses and prevent autoimmune diseases. Whether and how deoxyribonucleases respond to DNA virus infection are largely elusive. In this study, HSV-1 infection significantly upregulated and activated DNASE1L3. In vitro , DNASE1L3 overexpression upregulated the production of type I interferons and pro-inflammatory cytokines, enhanced IRF3 phosphorylation, and dampened viral replication whereas DNASE1L3 deficiency caused the opposite phenotypes. In vivo , Dnase1l3 knockout impaired innate immunity against HSV-1 and led to an early onset of death and low survival rate of mice. Mechanistically, DNASE1L3 enhanced the activation of cGAS-STING pathway through novel mechanisms. On one hand, DNASE1L3 bound to STING, enhanced its oligomerization and the recruitment of TBK1 independent of the nuclease activity. On the other hand, DNASE1L3 facilitated the release of HMGB1, and cGAS from chromatin dependent on the nuclease activity, which ultimately augmented cGAS oligomerization and cGAMP production. Our study revealed novel roles of DNASE1L3 and the underlying mechanisms coordinating innate immune responses to self-DNA and viral DNA.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1806552