Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Herpes simplex virus (HSV) is the main cause of viral encephalitis in the Western world, and the type I interferon (IFN) system is important for antiviral control in the brain. Here, we have compared Ifnb induction in mixed murine brain cell cultures by a panel of HSV1 mutants, each devoid of one mechanism to counteract the IFN-stimulating cGAS-STING pathway. We found that a mutant lacking the deubiquitinase (DUB) activity of the VP1-2 protein induced particularly strong expression of Ifnb and IFN-stimulated genes. HSV1 ΔDUB also induced elevated IFN expression in murine and human microglia and exhibited reduced viral replication in the brain. This was associated with increased ubiquitination of STING and elevated phosphorylation of STING, TBK1, and IRF3. VP1-2 associated directly with STING, leading to its deubiquitination. Recruitment of VP1-2 to STING was dependent on K150 of STING, which was ubiquitinated by TRIM32. Thus, the DUB activity of HSV1 VP1-2 is a major viral immune-evasion mechanism in the brain.

Original publication




Journal article


The Journal of experimental medicine

Publication Date





Department of Biomedicine, Aarhus University, Aarhus, Denmark.


Brain, Microglia, Cells, Cultured, Cytoplasm, Animals, Mice, Inbred C57BL, Humans, Herpesvirus 1, Human, Nucleotidyltransferases, Lysine, Interferon Type I, Membrane Proteins, Ubiquitin, Viral Proteins, DNA, Viral, Virus Replication, Signal Transduction, Mutation, Ubiquitination, HEK293 Cells, Deubiquitinating Enzymes, Protein Serine-Threonine Kinases