Abstract
Necroptosis complements apoptosis as a host defense pathway to stop virus infection. Herpes simplex virus shows a propensity to trigger necroptosis of mouse cells and mice even though cell death is blocked in human cells through UL39-encoded ICP6. This ribonucleotide reductase large subunit (R1) nucleates RHIM-dependent oligomerization of RIP3 kinase (RIPK3, also known as RIP3) in mouse cells but inhibits activation in cells from the natural human host. By interrogating the comparative behavior of ICP6-deficient viruses in mouse and human cells, here we unveil virus-induced necroptosis mediated by Z-DNA-binding protein 1 (ZBP1, also known as DAI). ZBP1 acts as a pathogen sensor to detect nascent RNA transcripts rather than input viral DNA or viral DNA generated through replication. Consistent with the implicated role of virus-induced necroptosis in restricting infection, viral pathogenesis is restored in Zbp1−/−, Ripk3−/− and Mlkl−/− mice. Thus, in addition to direct activation of RIPK3 via ICP6, HSV1 infection in mice and mouse cells triggers virus-induced necroptosis through ZBP1. Importantly, virus-induced necroptosis is also induced in human HT-29 cells by ICP6 mutant viruses; however, ZBP1 levels must be elevated for this pathway to be active. Thus, our studies reveal a common, species-independent role of this nucleic acid sensor to detect the presence of this virus. HSV1 ICP6 functions as a bona fide RHIM signaling inhibitor to block virus-induced necroptosis in its natural host. Altogether, ZBP1-dependent restriction of herpesvirus infection emerges as a potent antiviral armament of the innate immune system.
Highlights
Programmed necrosis, or necroptosis, has been recognized for contributions to antiviral host defense and inflammatory tissue damage
We find that ICP6 RIP homotypic interaction motif (RHIM) mutant HSV1 triggers virus-induced ZBP1/RIPK3/mixed-lineage kinase domain-like (MLKL)-dependent necroptosis in both mouse and human cells, thereby establishing the role of ZBP1 as an evolutionarily conserved sensor of HSV1 in both species
We observed RIPK3-dependent death of mouse cells infected with ICP6 mutant virus[20]
Summary
Programmed necrosis, or necroptosis, has been recognized for contributions to antiviral host defense and inflammatory tissue damage. This pathway is mediated by receptor-interacting protein (RIP) kinase (RIPK)3-dependent phosphorylation of mixed-lineage kinase domain-like (MLKL), a pseudokinase[1,2,3,4]. Guo et al Cell Death and Disease (2018)9:816 and 2, like the MCMV M45-encoded R1 sequence homolog, blocks RHIM-dependent pro-necrotic signal transduction in cells from its natural human host[13,14]. ZBP1 was implicated as a pathogen sensor capable of recognizing HSV1 DNA in mouse cells[15], along with cGAS and STING16–18. ZBP1 functions as crucial adaptor for RHIM-dependent activation of RIPK3-. Evidence is accumulating to suggest that ZBP1 senses accumulation of RNA rather than
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
