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Protein-S-Nitrosylation of Viral Proteins is A Universal Anti-Viral Mechanism
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Murphy, Eain
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Fall 2025
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2025-08-27
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Innate immune pathways like the cGAS/STING pathway are essential in the production of interferons to inhibit viral infections. DNA viruses have evolved measures to counteract our innate immune pathways. Common DNA viruses like Human Cytomegalovirus (HCMV), Human-Papillomavirus (HPV) and Adenovirus (AdV) each encode proteins that limit innate immunity. HCMV encoded pp71 and pp65 antagonize STING and cGAS, respectively. HPV encoded E7 and AdV encoded E1A both antagonize STING and diminish interferon response. However, the infected host cell has developed countermeasures to limit the activity of these pro-viral proteins. These mechanisms include the direct modification of viral proteins by post-translational modifications (PTMs). Herein, we postulate that a potent but relatively understudied PTM, called protein-S-nitrosylation, may serve as a universal anti-viral mechanism. We previously reported that protein-S-nitrosylation of pp71 undermines its ability to antagonize STING activation. Here we report that pp65 which undermines the cGAS/STING pathway is protein-S-nitrosylated, and this PTM limits the functions of this HCMV virulence factor. Mutations of the amino acids for protein-S-nitrosylation on pp65 from serine to cysteine thus blocking this PTM, resulted in the viral protein inhibiting the induction of the STING pathway with higher efficiency compared to WT. Further, nitrosylation deficient pp65 expression resulted in a reduced ability to phosphorylate IRF3 and TBK1 which led to a decrease in interferon beta secretion. This suggests protein-S-nitrosylation may function as a potent countermeasure to HCMV infection.
To determine if nitrosylation is a universal inhibitory mechanism for viruses beyond HCMV, we developed stable cell lines that express WT and serine mutant AdV E1A and HPV E7. We confirmed that E1A and E7 are both protein-S-nitrosylated and observed that nitrosylation deficient isoforms of these proteins result in diminished levels of interferon beta and a reduction in IRF3 phosphorylation upon STING induction. Further these proteins can complement the STING dependent inhibition of a pp71 HCMV. In sum out data suggests that protein-S-nitrosylation of viral proteins may serve as a universal anti-viral mechanism in viral infection and highlights the need to understand nitrosylation as an anti-viral mechanism for the development of novel therapeutics.
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