abstract.txt

Title: β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein
Text:
The cGAS/STING-mediated DNA-sensing signaling pathway is crucial
for interferon (IFN) production and host antiviral
responses. Herpes simplex virus I (HSV-1) is a DNA virus that has
evolved multiple strategies to evade host immune responses. Here,
we demonstrate that the highly conserved β-catenin protein in the
Wnt signaling pathway is an important factor to enhance the
transcription of type I interferon (IFN-I) in the cGAS/STING
signaling pathway, and the production of IFN-I mediated by
β-catenin was antagonized by HSV-1 US3 protein via its kinase
activity. Infection by US3-deficienct HSV-1 and its kinase-dead
variants failed to downregulate IFN-I and IFN-stimulated
gene (ISG) production induced by β-catenin. Consistent with this,
absence of β-catenin enhanced the replication of US3-deficienct
HSV-1, but not wild-type HSV-1. The underlying mechanism was the
interaction of US3 with β-catenin and its hyperphosphorylation of
β-catenin at Thr556 to block its nuclear translocation. For the
first time, HSV-1 US3 has been shown to inhibit IFN-I production
through hyperphosphorylation of β-catenin and to subvert host
antiviral innate immunity.IMPORTANCE Although increasing evidence
has demonstrated that HSV-1 subverts host immune responses and
establishes lifelong latent infection, the molecular mechanisms
by which HSV-1 interrupts antiviral innate immunity, especially
the cGAS/STING-mediated cellular DNA-sensing signaling pathway,
have not been fully explored. Here, we show that β-catenin
promotes cGAS/STING-mediated activation of the IFN pathway, which
is important for cellular innate immune responses and intrinsic
resistance to DNA virus infection. The protein kinase US3
antagonizes the production of IFN by targeting β-catenin via its
kinase activity. The findings in this study reveal a novel
mechanism for HSV-1 to evade host antiviral immunity and add new
knowledge to help in understanding the interaction between the
host and HSV-1 infection.

Keywords: HSV-1; US3; type I IFN; β-catenin.