Linker histone H1.2 inhibits HSV-1-induced IFN response via cGAS

Linker histone H1.2 (H1.2), as a member of the histone H1 family involved in many cellular physiological regulatory functions, plays a vital role in maintaining nucleosome and chromatin stability. Cyclic GMP-AMP synthase (cGAS) is a critical cytoplasmic DNA sensor that activates the downstream STING pathway by synthesizing 2'3'-cGAMP, which, in turn, triggers IFN-I response following double-stranded DNA virus infection. This study demonstrates that histone H1.2 is an essential negative regulator of cGAS, inhibiting antiviral immunity during HSV-1 infection. Mechanistically, H1.2 affects the activity of the Lys240 site of cGAS to affect the combination of cGAS with chromatin and promotes the degradation of cGAS in the nucleus by recruiting TRIM28, finally suppressing its IFN response. Moreover, HSV-1 infection downregulates H1.2 expression by reducing the mRNA levels of its transcription factor Sp1, thus allowing cGAS release to activate type I interferon signaling. Additionally, plicamycin, a selective inhibitor of Sp1, can reduce H1.2 expression and enhance antiviral immunity in mice against HSV-1 infection. These findings elucidate the function and regulatory mechanisms of the Sp1-H1.2-cGAS axis in innate immunity and propose new targets and strategies for antiviral drug development.IMPORTANCEPrevious studies on histone H1.2 mainly focused on its function of DNA damage repair and chromatin stability. However, our research found the new function and mechanism of H1.2 in anti-infection immune regulation and confirmed H1.2 as an important negative regulatory molecule responsible for inhibition of cGAS, the important sensor in pathogenic recognition. In the nucleus, H1.2 maintained the inactive state of cGAS by promoting its combination to chromatin and recruiting TRIM28 to degrade the inactive cGAS. We revealed the mechanism of host cells regulating antiviral immunity through the Sp1-H1.2-cGAS axis and found plicamycin could be used as a potential anti-infective drug. These data may offer important reference value for innate immune research.